Considerations on COM(2023)192 - Union code relating to medicinal products for human use

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dossier COM(2023)192 - Union code relating to medicinal products for human use.
document COM(2023)192 EN
date April 26, 2023
 
(1) The Union general pharmaceutical legislation was established in 1965 with the dual objective of safeguarding public health and harmonising the internal market for medicines. It has developed considerably since then, but these overarching objectives have guided all revisions. The legislation governs the granting of marketing authorisations for all medicines for human use by defining conditions and procedures to enter and remain on the market. A fundamental principle is that a marketing authorisation is granted only to medicines with a positive benefit-risk balance after assessment of their quality, safety and efficacy.

(2) The most recent comprehensive revision took place between 2001 and 2004 while targeted revisions on post-authorisation monitoring (pharmacovigilance) and on falsified medicines were adopted subsequently. In the almost 20 years since the last comprehensive revision, the pharmaceutical sector has changed and has become more globalised, both in terms of development and manufacture. Moreover, science and technology have evolved at a rapid pace. However, there continues to be unmet medical needs, i.e. diseases without or only with suboptimal treatments. Moreover, some patients may not benefit from innovation because medicines may be unaffordable or not placed on the market in the Member State concerned. There is also a greater awareness of the environmental impact of medicines. More recently, the COVID-19 pandemic has stress tested the framework.

(3) This revision is part of the implementation of the Pharmaceutical strategy for Europe and aims to promote innovation, in particular for unmet medical needs, while reducing regulatory burden and the environmental impact of medicines; ensure access to innovative and established medicines for patients, with special attention to enhancing security of supply and addressing risks of shortages, taking into account the challenges of the smaller markets of the Union; and create a balanced and competitive system that keeps medicines affordable for health systems while rewarding innovation.

(4) This revision focuses on provisions relevant to achieve its specific objectives; therefore it covers all but provisions concerning falsified medicines, homeopathic and traditional herbal medicines. Nevertheless, for the sake of clarity, it is necessary to replace Directive 2001/83/EC of the European Parliament and of the Council0 with a new Directive. The provisions on falsified medicines, homeopathic medicines and traditional herbal medicines are therefore maintained in this Directive without changing their substance compared to previous harmonisations. However, in view of the changes in the governance of the Agency, the Herbal Committee is replaced by a working group.

(5) The essential aim of any rules governing the authorisation, manufacturing, supervision, distribution and use of medicinal products must be to safeguard public health. Such rules should also ensure the free movement of medicinal products and the elimination of obstacles to trade in medicinal products to all patients in the Union.

(6) The regulatory framework for medicinal products use should also take into account the needs of the undertakings in the pharmaceutical sector and trade in medicinal products within the Union, without jeopardising the quality, safety and efficacy of medicinal products.

(7) The EU and all its Member States as parties to the United Nations Convention on the Rights of Persons with Disabilities are bound by its provisions to the extent of their competences. This includes the right to access information as set out in Article 21 and the right to the enjoyment of the highest attainable standard of health without discrimination on the basis of disability as set in Article 25.

(8) This revision maintains the level of harmonisation that has been achieved. Where necessary and appropriate, it further reduces the remaining disparities, by laying down rules on the supervision and control of medicinal products and the rights and duties incumbent upon the competent authorities of the Member States with a view to ensuring compliance with legal requirements. In the light of experience gained on the application of the Union pharmaceutical legislation and the evaluation of its functioning, the regulatory framework need to be adapted to scientific and technological progress, the current market conditions and economic reality within the Union. Scientific and technological developments induce innovation and development of medicinal products, including for therapeutic areas where there is still unmet medical need. To harness these developments, the Union pharmaceutical framework should be adapted to meet scientific developments such as genomics, accommodate cutting edge medicinal products, e.g. personalised medicinal products and technological transformation such as data analytics, digital tools and the use of artificial intelligence. These adaptations also contribute to competitiveness of the Union pharmaceutical industry.

(9) Medicinal products for rare diseases and for children, should be subject to the same conditions as any other medicinal product concerning their quality, safety and efficacy, for example for what concerns the marketing authorisation procedures, quality and the pharmacovigilance requirements. However, specific requirements also apply to them considering their unique characteristics. Such requirements, which are currently defined in separate legislations, should be integrated in general pharmaceutical legal framework in order to ensure clarity and coherency of all the measures applicable to these medicinal products. Furthermore, as some medicinal products authorised for use in children are authorised by the Member States, specific provisions should be integrated in this Directive.

(10) The system of a directive and regulation for the general pharmaceutical legislation should be maintained to avoid fragmentation of national legislation on medicinal products for human use, given that the legislation is based on a system of national Member States and Union marketing authorisations. Member States national marketing authorisations are granted and managed on the basis of national law implementing the Union pharmaceutical law. The evaluation of the general pharmaceutical legislation has not shown that the choice of legal instrument has caused specific problems or created disharmonisation. In addition, a REFIT Platform0 opinion in 2019 showed that there was not support among the Member States to turn Directive 2001/83/EC into a Regulation.

(11) The Directive should work in synergy with the Regulation to enable innovation and promote competitiveness of the Union pharmaceutical industry, in particular SMEs. In this respect a balanced system of incentives is proposed that rewards innovation especially in areas of unmet medical need and innovation that reaches patients and improves access across the Union. To make the regulatory system more efficient and innovation-friendly the Directive also aims at reducing administrative burden and simplifying procedures for undertakings.

(12) The definitions and scope of Directive 2001/83/EC should be clarified in order to achieve high standards for the quality, safety and efficacy of medicinal products and to address potential regulatory gaps, without changing the overall scope, due to scientific and technological developments, e.g. low-volume products, bedside-manufacturing or personalised medicinal products that do not involve an industrial manufacturing process.

(13) To avoid the duplication of requirements for medicinal products in this Directive and in the Regulation, the general standards in regards to quality, safety and efficacy of medicinal products laid down in this Directive shall be applicable to medicinal products covered by national marketing authorisation and also to medicinal products covered by centralised marketing authorisation. Therefore, the requirements for an application for medicinal product are valid for both, also the rules on prescription status, product information, regulatory protection and rules on manufacturing, supply, advertising, supervision and other national requirements shall be applicable to medicinal products covered by centralised marketing authorisation.

(14) The determination of whether a product falls within the definition of a medicinal product must be made on a case-by-case basis taking into account the factors set out in this Directive, such as the product’s presentation or pharmacological, immunological or metabolic properties.

(15) In order to take account both of the emergence of new therapies and of the growing number of so-called ‘borderline’ products between the medicinal product sector and other sectors, certain definitions and derogations should be modified, so as to avoid any doubt as to the applicable legislation. With the same objective of clarifying situations when a product fully falls within the definition of a medicinal product and also meet the definition of other regulated products, the rules for medicinal products under this Directive apply. Furthermore, to ensure the clarity of applicable rules, it is also appropriate to improve the consistency of the terminology of the pharmaceutical legislation and clearly indicate the products excluded from the scope of this Directive.

(16) The new definition for a substance of human origin (SOHO) by the [SoHO Regulation] covers any substance collected from the human body in whatever manner, whether it contains cells or not and regardless of whether it meets the definition of ‘blood’, ‘tissue’ or ‘cell’, for example human breast milk, intestinal microbiota and any other SoHO that may be applied to humans in the future. Such substances of human origin, other than tissues and cells, may become SoHO derived medicinal products, other than ATMPs, when the SoHO is subject to an industrial process involving systematisation, reproducibility and operations performed on a routine basis or batch-wise resulting in a product of standardised consistency. When a process concerns extraction of an active ingredient from the SoHO, other than tissues and cells, or a transformation of a SoHO, other than tissues and cells, by changing its inherent properties, this should also be considered a SoHO derived medicinal product. When a process concerns concentrating, separating or isolating elements in the preparation of blood components, this should not be considered as changing their inherent properties.

(17) For avoidance of doubt, the safety and quality of human organs intended for transplantation are regulated only by Directive 2010/53/EU of the European Parliament and of the Council0, and the safety and quality of substances of human origin intended for medically assisted reproduction are regulated only by [SoHO Regulation or if not in force, Directive 2004/23/EC].

(18) Advanced therapy medicinal products that are prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient, should be excluded from the scope of this Directive whilst at the same time ensuring that relevant Union rules related to quality and safety are not undermined (‘hospital exemption’). Experience has shown that there are great differences in the application of hospital exemption among Member States. To improve the application of hospital exemption this Directive introduces measures for collection, reporting of data as well as review of these data yearly by the competent authorities and their publication by the Agency in a repository. Furthermore, the Agency should provide a report on the implementation of hospital exemption on the basis of contributions from Member States in order to examine whether an adapted framework should be established for certain less complex ATMPs that have been developed and used under the hospital exemption. When an authorisation for the manufacturing and use of an ATMP under hospital exemption is revoked because of safety concerns, the relevant competent authorities shall inform the competent authorities of other Member States. 

(19) This Directive should be without prejudice to the provisions of Council Directive 2013/59/Euratom0, including with respect to justification and optimisation of protection of patients and other individuals subject to medical exposure to ionising radiation. In the case of radiopharmaceuticals used for therapy, marketing authorisations, posology and administration rules have to notably respect that Directive’s requirements that exposures of target volumes are to be individually planned, and their delivery appropriately verified taking into account that doses to non-target volumes and tissues are to be as low as reasonably achievable and consistent with the intended therapeutic purpose of the exposure.

(20) In the interest of public health, a medicinal product should only be allowed to be placed on the market in the Union when the marketing authorisation has been granted to the medicinal product, and its quality, safety and efficacy have been demonstrated. However, exemption should be provided from this requirement in situations characterised by an urgent need to administer a medicinal product to address the specific needs of a patient, or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation that could cause harm. In particular, to fulfil special needs, Member States should be allowed to exclude from the provisions of this Directive medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorised healthcare professional and for use by an individual patient under their direct personal responsibility. Member States should be also allowed to temporarily authorise the distribution of an unauthorised medicinal product in response to a suspected or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation any of which could cause harm.

(21) Marketing authorisation decisions should be taken on the basis of the objective scientific criteria of quality, safety and efficacy of the medicinal product concerned, to the exclusion of economic or any other considerations. However, Member States should be able exceptionally to prohibit the use in their territory of medicinal products.

(22) The particulars and documentations that are to accompany an application for marketing authorisation for a medicinal product demonstrate that the therapeutic efficacy of the product overweight potential risks. The benefit-risk balance of all medicinal products will be assessed when they are placed on the market, and at any other time the competent authority deems appropriate.

(23) As market forces alone have proven insufficient to stimulate adequate research into, and the development and authorisation of, medicinal products for the paediatric population, a system of both obligations and rewards and incentives has been put in place.

(24) It is therefore necessary to introduce a requirement for new medicinal products or when developing paediatric indications of already authorised products covered by a patent or a supplementary protection certificate to present either the results of studies in the paediatric population in accordance with an agreed paediatric investigation plan or proof of having obtained a waiver or deferral, at the time of filing a marketing authorisation application or an application for a new therapeutic indication, new pharmaceutical form or new route of administration. However, in order to avoid exposing children to unnecessary clinical trials or due to the nature of the medicinal products, that requirement should not apply to generics or similar biological medicinal products and medicinal products authorised through the well-established medicinal use procedure, nor to homeopathic medicinal products and traditional herbal medicinal products authorised through the simplified registration procedures of this Directive.

(25) In order to ensure that the data supporting the marketing authorisation concerning the use of a product in children to be authorised under this regulation have been correctly developed, the competent authorities should check compliance with the agreed paediatric investigation plan and any waivers and deferrals at the validation step for marketing authorisation applications.

(26) In order to reward the compliance with all the measures included in the agreed paediatric investigation plan, for products covered by a supplementary protection certificate, if relevant information on the results of the studies conducted is included in the product information, a reward should be granted in the form of a six month extension of the supplementary protection certificate created by [Regulation (EC) No 469/2009 of the European Parliament and of the Council0- OP please replace reference by new instrument when adopted].

(27) Certain particulars and documentation that are normally to be submitted with an application for a marketing authorisation should not be required if a medicinal product is a generic medicinal product or a similar biological medicinal product (biosimilar) that is authorised or has been authorised in the Union. Both generic and biosimilar medicinal products are important to ensure access of medicinal products to a wider patient population and create a competitive internal market. In a joint statement authorities of the Member States confirmed that the experience with approved biosimilar medicinal products over the past 15 years has shown that in terms of efficacy, safety and immunogenicity they are comparable to their reference medicinal product and are therefore interchangeable and can be used instead of its reference product (or vice versa) or replaced by another biosimilar of the same reference product.

(28) Experience has shown that it is advisable to stipulate precisely the cases in which the results of toxicological and pharmacological tests or clinical studies do not have to be provided with a view to obtaining authorisation for a medicinal product that is essentially similar to an authorised product, while ensuring that innovative undertakings are not placed at a disadvantage. For these specified categories of medicinal products an abridged procedure allows applicants to rely on data submitted by previous applicants and therefore to submit only some specific documentation.

(29) For generic medicinal products only the equivalence of the generic medicinal product with the reference medicinal product has to be demonstrated. For biological medicinal products, only the results of comparability tests and studies are provided to the competent authorities. For hybrid medicinal products i.e. 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 extent necessary to establish a scientific bridge to the data relied upon in the marketing authorisation for the reference medicinal product. The same applies to bio-hybrids i.e. 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. In the latter two situations, the scientific bridge establishes that the active substance of the hybrid does not differ significantly in properties with regard to safety or efficacy. Where it differs significantly in respect of those properties, the applicant needs to submit a full application.

(30) Regulatory decision-making on the development, authorisation and supervision of medicines may be supported by access and analysis of health data, including real world data i.e. health data generated outside of clinical studies, where appropriate. The competent authorities should be able to use such data, including via the European Health Data Space interoperable infrastructure.

(31) Directive 2010/63/EU of the European Parliament and of the Council0 lays down provisions on the protection of animals used for scientific purposes based on the principles of replacement, reduction and refinement. Any study involving the use of animals, which provides essential information on the quality, safety and efficacy of a medicinal product, should take into account those principles of replacement, reduction and refinement, where they concern the care and use of live animals for scientific purposes, and should be optimised in order to provide the most satisfactory results whilst using the minimum number of animals. The procedures of such testing should be designed to avoid causing pain, suffering, distress or lasting harm to animals and should follow the available EMA and ICH guidelines. In particular, the marketing authorisation applicant and the marketing authorisation holder should take into account the principles laid down in Directive 2010/63/EU, including, where possible, use new approach methodologies in place of animal testing. These can include but are not limited to: in vitro models, such as microphysiological systems including organ-on-chips, (2D and 3D-) cell culture models, organoids and human stem cells-based models; in silico tools or read-across models.

(32) Procedures should be in place to facilitate joint animal testing, wherever possible, in order to avoid unnecessary duplication of testing using live animals covered by Directive 2010/63/EU. Marketing authorisation applicants and marketing authorisation holders should make all efforts to reuse animal study results and make the results obtained from animal studies publicly available. For abridged applications marketing authorisation applicants should refer to the relevant studies conducted for the reference medicinal product.

(33) With respect to clinical trials, in particular those conducted outside the Union, on medicinal products destined to be authorised within the Union, it should be verified, at the time of the evaluation of the marketing authorisation application, that these trials were conducted in accordance with the principles of good clinical practice and the ethical requirements equivalent to the provisions of Regulation (EU) 536/2014 of the European Parliament and of the Council0.

(34) There is the possibility under certain circumstances for marketing authorisations to be granted, subject to specific obligations or conditions, on a conditional basis or under exceptional circumstances. The legislation should allow under similar circumstances for medicinal products with a standard marketing authorisation for new therapeutic indications to be authorised on a conditional basis or under exceptional circumstances. The products authorised on a conditional basis or under exceptional circumstances should in principle satisfy the requirements for a standard marketing authorisation with the exception of the specific derogations or conditions outlined in the relevant conditional or exceptional marketing authorisation and shall be subject to specific review of the fulfilment of the imposed specific conditions or obligations. The grounds for refusal of a marketing authorisation should apply mutatis mutandis for such cases.

(35) With the exception of those medicinal products that are subject to the centralised authorisation procedure established by [revised Regulation (EU) No. 726/2004], a marketing authorisation for a medicinal product should be granted by a competent authority in one Member State. In order to avoid unnecessary administrative and financial burdens for applicants and competent authorities, a full in-depth assessment of an application for the authorisation of a medicinal product should be carried out only once. It is appropriate therefore to lay down special procedures for the mutual recognition of national authorisations. Moreover, it should be possible to submit the same application in parallel in several Member States for the purpose of a common assessment under the lead of one of the Member States concerned.

(36) Moreover, rules should be established under those procedures to resolve any disagreements between competent authorities in a coordination group for mutual recognition and decentralised procedures medicinal products (‘the coordination group’) without undue delay. In the event of a disagreement between Member States about the quality, the safety or the efficacy of a medicinal product, a scientific evaluation of the matter should be undertaken according to a Union standard, leading to a single decision on the area of disagreement binding on the Member States concerned. Whereas this decision should be adopted by a rapid procedure ensuring close cooperation between the Commission and the Member States.

(37) In certain cases of major disagreement that cannot be solved, the case should be escalated and be subject to a scientific opinion of the Agency, which is then implemented through a Commission Decision.

(38) In order to better protect public health and avoid any unnecessary duplication of effort during the examination of application for a marketing authorisation for medicinal products, Member States should systematically prepare assessment reports in respect of each medicinal product that is authorised by them, and exchange the reports upon request. Furthermore, a Member State should be able to suspend the examination of an application for authorisation to place a medicinal product on the market that is currently under active consideration in another Member State with a view to recognising the decision reached by the latter Member State.

(39) In the interest of as broad as possible access to medicinal products, a Member State that has an interest in receiving access to a particular medicinal product undergoing authorisation through the decentralised and mutual recognition procedures should be able to opt-into that procedure.

(40) In order to increase availability of medicinal products, in particular on smaller markets, it should, in cases where an applicant does not apply for an authorisation for a medicinal product in the context of the mutual-recognition procedure in a given Member State, be possible for that Member State, for justified public health reasons, to authorise the placing on the market of the medicinal product.

(41) In the case of generic medicinal products of which the reference medicinal product has been granted a marketing authorisation under the centralised procedure, applicants seeking marketing authorisation should be able to choose either of the two procedures, on certain conditions. Similarly, the mutual-recognition or decentralised procedure should remain available as an option for certain medicinal products, even if they represent a therapeutic innovation or are of benefit to society or to patients. Since generic medicines account for a major part of the market in medicinal products, their access to the Union market should be facilitated in the light of the experience acquired, therefore, the procedures to include other Member States concerned to such procedure should be further simplified.

(42) The simplification of procedures should not have an impact on standards or the quality of scientific evaluation of medicinal products to guarantee the quality, safety and efficacy and therefore, the scientific evaluation period should remain. However, the reduction of overall period for marketing authorisation procedure from 210 days to 180 days is foreseen.

(43) Member States should ensure adequate funding of competent authorities to carry out their tasks under this Directive and [revised Regulation (EU) 726/2004]. In addition, Member States should ensure adequate resources are assigned by the competent authorities for the purpose of their contributions to the work of the Agency, taking into account the cost-based remuneration they receive from the Agency.

(44) As regards access to medicinal products, previous amendments to the Union pharmaceutical legislation have addressed this issue by providing for accelerated assessment of marketing authorisation applications or by allowing conditional marketing authorisation for medicinal products for unmet medical need. While these measures accelerated the authorisation of innovative and promising therapies, these medicinal products do not always reach the patient and patients in the Union still have different levels of access to medicinal products. Patient access to medicinal products depends on many factors. Marketing authorisation holders are not obliged to market a medicinal product in all Member States; they may decide not to market their medicinal products in, or withdraw them from, one or more Member States. National pricing and reimbursement policies, the size of the population, the organisation of health systems and national administrative procedures are other factors influencing market launch and patient access.

(45) Addressing unequal patient access and affordability of medicinal products has become a key priority of the Pharmaceutical Strategy for Europe, as also highlighted by Council conclusions0 and a resolution of the European Parliament0. Member States called for revised mechanisms and incentives for development of medicinal products tailored to the level of unmet medical need, while ensuring health system sustainability, patient access and availability of affordable medicinal products in all Member States.

(46) Access also comprise affordability. In this regard, the Union pharmaceutical legislation respects the competence of the Member States in terms of pricing and reimbursement. In a complementary manner, it aims to have a positive impact on affordability and sustainability of health systems with measures that support competition from generic and biosimilar medicinal products. The competition from generic and biosimilar medicinal products should also, in turn, increase patient access to medicinal products.

(47) To ensure dialogue among all actors in the medicines lifecycle, discussions on policy issues related to the application of the rules related to prolongation of regulatory data protection for market launch shall take place in the Pharmaceutical Committee. The Commission may invite bodies responsible for health technology assessment as referred to in Regulation (EU) 2021/2282 or national bodies responsible for pricing and reimbursement, as required, to participate in the deliberations of the Pharmaceutical Committee.

(48) While pricing and reimbursement decisions are a Member State competence, the Pharmaceutical Strategy for Europe announced actions to support cooperation of Member States to improve affordability. The Commission has transformed the group of National Competent Authorities on Pricing and Reimbursement and public healthcare payers (NCAPR) from an ad-hoc forum to a continuous voluntary cooperation with the aim to exchange information and best practices on pricing, payment and procurement policies to improve the affordability and cost-effectiveness of medicines and health system’s sustainability. The Commission is committed to stepping up this cooperation and further supporting information exchange among national authorities, including on public procurement of medicines, while fully respecting the competences of Member States in this area. The Commission may also invite NCAPR members to participate in deliberations of the Pharmaceutical Committee on topics that may have an impact on pricing or reimbursement policies, such as the market launch incentive.

(49) Joint procurement, whether within a country or across countries, can improve access, affordability, and security of supply of medicines, in particular for smaller countries. Member States interested in joint procurement of medicines can make use of Directive 2014/24/EU0, which sets out purchasing procedures for public buyers, the Joint Procurement Agreement0 and the proposed revised Financial Regulation0. Upon request from the Member States the Commission may support interested Member States by facilitating coordination to enable access to medicines for patients in the Union as well as information exchange, in particular for medicines for rare and chronic diseases.

(50) The establishment of a criteria-based definition of ‘unmet medical need’ is required to incentivise the development of medicinal products in therapeutic areas that are currently underserved. To ensure that the concept of unmet medical need reflects scientific and technological developments and current knowledge in underserved diseases, the Commission should specify and update using implementing acts, the criteria of satisfactory method of diagnosis, prevention or treatment, ‘remaining high morbidity or mortality’, ‘relevant patient population’ following scientific assessment by the Agency. The Agency will seek input from a broad range of authorities or bodies active along the lifecycle of medicinal products in the framework of the consultation process established under the [revised Regulation (EC) No 726/2004] and also take into account scientific initiatives at EU level or between Member States related to analysing unmet medical needs, burden of disease and priority setting for research and development. The criteria for ‘unmet medical need’ can be subsequently used by Member States to identify specific therapeutic areas of interest.

(51) The inclusion of new therapeutic indications to an authorised medicinal products contributes to the access of patients to additional therapies and therefore should be incentivised.

(52) For the initial marketing authorisation application for medicinal products containing a new active substance, the submission of clinical trials that include as a comparator an evidence-based existing treatment should be incentivised, in order to foster the generation of comparative clinical evidence that is relevant and can accordingly support subsequent health technology assessments and decisions on pricing and reimbursement by Member States.

(53) A marketing authorisation holder should ensure the appropriate and continuous supply of a medicinal product throughout its lifetime irrespective of whether that medicinal product is covered by a supply incentive or not.

(54) Micro, small and medium-sized enterprises (‘SMEs’), not-for-profit entities or entities with limited experience in the Union system should benefit from additional time to market a medicinal product in the Member States where the marketing authorisation is valid for the purposes of receiving additional regulatory data protection.

(55) When applying the provisions on market launch incentives, marketing authorisation holders and Member States should do their utmost to achieve a mutually agreed supply of medicinal products in accordance with the needs of the Member State concerned, without unduly delaying or hindering the other party from enjoying its rights under this Directive.

(56) Member States have the possibility to waive the condition of launch in their territory for the purpose of the prolongation of data protection for market launch. This can be done through a statement of non-objection to prolong the period of regulatory data protection. This is expected to be the case particularly in situations where launch in a particular Member State is materially impossible or because there are special reasons why a Member State wishes that launch take place later.

(57) The issuing of documentation from the Member States as regards the prolongation of data protection for the purpose of supply of medicinal products in all Member States where a marketing authorisation is valid, in particular the waiver to the conditions for such prolongation, does not affect at any time the powers of the Member States as regards the supply, setting of prices for medicinal products or their inclusion in the scope of national health insurance schemes. Member States do not waive the possibility to request release or supply of the product concerned at any time before, during or after the prolongation of the data protection period.

(58) An alternative way of demonstrating supply relates to the inclusion of medicinal products in a positive list of medicinal products covered by the national health insurance system in accordance with Directive 89/105/EEC. The related negotiations between companies and the Member State should be conducted in good faith.

(59) A Member State that considers that the conditions of supply have not been met for its territory should provide a reasoned statement of non-compliance at the latest in the Standing Committee on Medicinal Products for Human Use procedure of the variation linked to the provision of the relevant incentive.

(60) The Commission and Member States shall continuously monitor any data and learnings from the application of the incentives system in order to improve, including through implementing acts, how these provisions are applied. The Commission shall establish a list of national contact points in this regard.

(61) When a compulsory licence has been granted by a relevant authority in the Union to tackle a public health emergency, regulatory data protection may, if still in force, prevent the effective use of the compulsory licence as they impede the authorisation of generic medicinal products, and thus access to the medicinal products needed to address the crisis. For this reason, data and market protection should be suspended when a compulsory licence has been issued to tackle a public health emergency. Such a suspension of the regulatory data protection should be allowed only in relation to the compulsory licence granted and its beneficiary. The suspension shall comply with the objective, the territorial scope, the duration and the subject matter of the granted compulsory licence.

(62) The suspension of the regulatory data protection should be granted only for the duration of the compulsory licence. A ‘suspension‘ of data and market protection in cases of public health emergency shall mean that data and market protection shall produce no effect in relation to the particular licensee of the compulsory licence while that compulsory licence is in effect. When the compulsory licence ends, the data and market protection shall resume their effect. The suspension should not result in an extension of the original duration.

(63) It is currently possible for applicants for marketing authorisation of generic, biosimilar, hybrid and bio-hybrid medicinal products to conduct studies, trials and the subsequent practical requirements necessary to obtain regulatory approvals for those medicinal products during the term of protection of the patent or Supplementary Protection Certificate (SPC) of the reference medicinal product, without this being considered patent or SPC infringement. The application of this limited exemption is however fragmented across the Union and it is considered necessary, in order to facilitate the market entry of generic, biosimilar, hybrid and bio-hybrid medicinal products that rely on a reference medicinal product, to clarify its scope in order to ensure a harmonised application in all Member States, both in terms of beneficiaries and in terms of activities covered. The exemption must be confined to conduct studies and trials and other activities needed for the regulatory approval process, health technology assessment and pricing reimbursement request, even though this may require substantial amounts of test production to demonstrate reliable manufacturing. During the term of protection of the patent or SPC of the reference medicinal product, there can be no commercial use of the resulting final medicinal products obtained for the purposes of the regulatory approval process.

(64) It will allow, inter alia, to conduct studies to support pricing and reimbursement as well as the manufacture or purchase of patent protected active substances for the purpose of seeking marketing authorisations during that period, contributing to the market entry of generics and biosimilars on day one of loss of the patent or SPC protection.

(65) The competent authorities should refuse the validation for an application for a marketing authorisation referring to data of a reference medicinal product only on the basis of the grounds set out in this Directive. The same applies to any decision to grant, vary, suspend, restrict or revoke the marketing authorisation. The competent authorities cannot base their decision on any other grounds. In particular, those decisions cannot be based on the patent or SPC status of the reference medicinal product.

(66) In order to address the challenge of antimicrobial resistance, antimicrobials should be packaged in quantities that are appropriate for the therapy cycle relevant for that product and national rules on antimicrobial subject to prescription ensure that they are dispensed in a way that corresponds to the quantities described by the prescription.

(67) The provision of information to healthcare professionals and to patients on the appropriate use, storage and disposal of antimicrobials is a joint responsibility of marketing authorisation holders and of Member States who should ensure appropriate collection system for all medicinal products.

(68) While this Directive restricts the use of antimicrobials by setting certain categories of antimicrobials under prescription status, due to the growing antimicrobial resistance in the Union, competent authorities of the Member States should consider further measures for example expanding the prescription status of antimicrobials or the mandatory use of diagnostic tests before prescription. Competent authorities of the Member States should consider such further measures according to the level of antimicrobial resistance in their territory and the needs of patients.

(69) The pollution of waters and soils with pharmaceutical residues is an emerging environmental problem, and there is scientific evidence that the presence of those substances in the environment from their manufacturing, use and disposal poses a risk to the environment and public health. The evaluation of the legislation showed that strengthening of existing measures to reduce the impact of medicinal products' lifecycle on the environment and public health is required. Measures under this Regulation complement the main environmental legislation, in particular the Water Framework Directive (2000/60/EC0), the Environmental Quality Standard Directive (2008/105/EC0) the Groundwater Directive (2006/118/EC0), the Urban Wastewater Treatment Directive (91/271/EEC0), the Drinking Water Directive (2020/21840) and the Industrial Emissions Directive (2010/75/EU0).

(70) Marketing authorisation applications for medicinal products in the Union should include an Environmental Risk Assessment (ERA) and risk mitigation measures. If the applicant fails to submit a complete or sufficiently substantiated environmental risk assessment or they do not propose risk mitigation measures to sufficiently address the risks identified in the environmental risk assessment, the marketing authorisation should be refused. The ERA should be updated when new data or knowledge about relevant risks become available.

(71) Marketing authorisation applicants should take into account environmental risk assessment procedures of other EU legal frameworks that may apply to chemicals dependent on their use. Further to this Regulation, there are four main other frameworks: (i) Industrial chemicals (REACH, (Regulation (EC) No 1907/2006); (ii) Biocides (Regulation (EC) No 528/2012); (iii) Pesticides (Regulation (EC) No 1107/2009); and (iv) Veterinary medicines (Regulation (EU) 2019/6)). As a part of the Green Deal, the Commission has proposed a ‘one-substance one-assessment’ (OS-OA) approach for chemicals0, in order to increase the efficiency of the registration system, reduce costs and unnecessary animal testing.

(72) The emissions and discharges of antimicrobials to the environment from manufacturing sites may lead to antimicrobial resistance (“AMR”), which is a global concern regardless where the emissions and discharges take place. Therefore, the ERA scope should be extended to cover the risk of AMR selection during the entire life cycle of antimicrobials, including manufacturing.

(73) The proposal also includes provisions for a risk-based approach regarding the ERA obligations of marketing authorisation holders before October 2005 and the setting-up of an ERA monograph system for active substances. This ERA monograph system should be available to applicants for use when conducting an ERA for a new application.

(74) For medicinal products authorised prior to October 2005, without any ERA, specific provisions should be introduced to set up a risk based prioritisation programme for the ERA submission or update by the market authorisation holders.

(75) Cyprus, Ireland, Malta and Northern Ireland have historically relied on the supply of medicinal products from or through parts of the United Kingdom other than Northern Ireland. Following the withdrawal of the United Kingdom of Great Britain and Northern Ireland from the European Union and the European Atomic Energy Community, to prevent shortages of medicinal products and ultimately to ensure a high level of public health protection, specific derogations to this Directive need to be included for medicinal products supplied to Cyprus, Ireland, Malta and Northern Ireland from or through parts of the United Kingdom other than Northern Ireland. In order to ensure uniform application of Union law in the Member States, the derogations applicable in Cyprus, Ireland and Malta should be of a temporary nature only.

(76) To ensure that all children in the Union have access to the products specifically authorised for paediatric use, when an agreed paediatric investigation plan has led to the authorisation of a paediatric indication for a product already marketed for other therapeutic indications, the marketing authorisation holder should be obliged to place the product in the same markets within two years of the date of approval of the indication.

(77) It is necessary in the interest of public health to ensure the continuing availability of safe and effective medicinal products authorised for paediatric indications. Therefore, if a marketing authorisation holder intends to withdraw such a medicinal product from the market then arrangements should be in place so that the paediatric population can continue to have access to the medicinal product in question. In order to help achieve this, the Agency should be informed in good time of any such intention and should make that intention publicly available.

(78) To avoid unnecessary administrative and financial burdens both for the marketing authorisation holders and the competent authorities, certain streamlining measures should be introduced, in line with the digital by default principle. Electronic application for marketing authorisation and for variations to the terms of the marketing authorisation should be introduced.

(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.

(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.

(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.

(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.

(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.

(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.

(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 Council0. 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.

(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].

(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.

(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.

(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.

(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.

(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.

(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.

(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, 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 a certification scheme also for additional 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, radiopharmaceutical precursors and active substance intermediates, when the intermediate is a chemical active substance by itself or used in conjugation with a biological substance.

(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.

(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.

(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.

(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) 2016/6790 and Regulation (EU) 2018/17250 of the European Parliament and of the Council.

(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.

(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.

(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.

(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.

(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.

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

(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 Council0, and restricted to those authorised in accordance with Regulation (EC) No 1333/2008 of the European Parliament and of the Council on food additives0, for which specifications are laid down in Commission Regulation (EU) No 231/20120. 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.

(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.

(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.

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

(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.

(109) There may be cases where manufacturing or testing steps of medicinal products need to take place in sites close to patients, for example advanced therapy medicinal products with short shelf-life. In such cases, these manufacturing or testing steps may need to be decentralised to multiple sites to reach patients across the Union. When the manufacturing or testing steps are decentralised, they should be carried out under the responsibility of the qualified person of an authorised central site. The decentralised sites should not require a separate manufacturing authorisation from the one granted to the relevant central site but should be registered by the competent authority of the Member State in which the decentralised site is established. In the case of medicinal products containing, consisting or derived from autologous SoHO, the decentralised sites have to be registered as a SoHO entity as defined in and pursuant to [SoHO Regulation] for the activities of donor review and eligibility assessment, donor testing and collection, or just for collection in the case of products manufactured for autologous use.

(110) The quality of medicinal products manufactured or available in the Union should be guaranteed by requiring that the active substances used in their composition comply with the principles of good manufacturing practice in relation to those medicinal products. It has proved necessary to reinforce the Union provisions on inspections and to compile a Union database of the results of those inspections.

(111) Verification of compliance with the legal requirements of manufacturing, distribution and use of medicinal products by relevant entities through a system of supervision, is of fundamental importance to ensure that the objectives of this Directive are effectively achieved. Therefore, the competent authorities of the Member States should have the power to perform on site or remote inspections, as part of the system of supervision at all stages of manufacturing, distribution and use of medicinal products or active substances and rely on the outcome of inspections conducted by trusted third countries competent authorities. To preserve the effectiveness of the inspections, the competent authorities should have the possibility to perform joint inspections and also, where necessary, unannounced inspections.

(112) The frequency of controls should be established by the competent authorities having regard to the risk and to the level of compliance expected in different situations. That approach should allow those competent authorities to allocate resources where the risk is the highest. In some cases, the system of supervision should be applied irrespective of the level of risk or suspected non-compliance, for example prior to granting manufacturing authorisations.

(113) Within the procedure for 'Certification of Suitability to the monographs of the European Pharmacopoeia' the European Directorate for the Quality of Medicines and Healthcare verifies by means of inspections whether the data submitted by the applicant established by the Council of Europe confirms the suitability of monographs to control the chemical purity, microbiological quality and TSE risk (if relevant). It also verifies whether the manufacturing complies with good manufacturing practice for active substances. Depending of the outcome of the inspection, a certificate of compliance or non-compliance of good manufacturing practice, is issued by the European Directorate for the Quality of Medicines and Healthcare or by the Member State participating in the inspection.

(114) Each undertaking that manufactures or imports medicinal products should set up a mechanism to ensure that all information supplied about a medicinal product conforms to the approved conditions of use.

(115) The conditions governing the supply of medicinal products to the public should be harmonised.

(116) In this connection persons moving around within the Union have the right to carry a reasonable quantity of medicinal products lawfully obtained for their personal use. It should also be possible for a person established in one Member State to receive from another Member State a reasonable quantity of medicinal products intended for their personal use.

(117) By virtue of [revised Regulation (EC) No 726/2004], certain medicinal products are the subject of a Union marketing authorisation. In this context, the prescription status of medicinal products covered by a Union marketing authorisation needs to be established. It is therefore important to set the criteria on the basis of which Union decisions will be taken.

(118) It is therefore appropriate to harmonise the basic principles applicable to the prescription status of medicinal products in the Union or in the Member State concerned, while taking as a starting point the principles already established on this subject by the Council of Europe as well as the work of harmonisation completed within the framework of the United Nations, concerning psychotropic or narcotic substances - the United Nations Single Convention of 1961 on narcotic drugs and Convention on Psychotropic Substances of 1971.

(119) Many operations involving the wholesale distribution of medicinal products may cover several Member States simultaneously.

(120) It is necessary to exercise control over the entire chain of distribution of medicinal products, from their manufacture or import into the Union through to supply to the public, so as to guarantee that such products are stored, transported and handled in suitable conditions. The requirements that should be adopted for this purpose will considerably facilitate the withdrawal of defective products from the market and allow more effective efforts against counterfeit products.

(121) Any person involved in the wholesale distribution of medicinal products should be in possession of a special authorisation. Pharmacists and persons authorised to supply medicinal products to the public, and who confine themselves to this activity, should be exempt from obtaining this authorisation. It is however necessary, in order to control the complete chain of distribution of medicinal products, that pharmacists and persons authorised to supply medicinal products to the public keep records showing transactions in products received.

(122) Marketing authorisation is to be subject to certain essential conditions and it is the responsibility of the Member State concerned to ensure that such conditions are met; whereas each Member State is to recognize authorisations granted by other Member States.

(123) Certain Member States impose on wholesalers who supply medicinal products to pharmacists and on persons authorised to supply medicinal products to the public certain public service obligations. Those Member States should be able to continue to impose those obligations on wholesalers established within their territory. They should also be able to impose them on wholesalers in other Member States on condition that they do not impose any obligation more stringent than those that they impose on their own wholesalers and provided that such obligations may be regarded as warranted on grounds of public health protection and are proportionate in relation to the objective of such protection.

(124) Rules should be laid down as to how the labelling and package leaflets are to be presented.

(125) The provisions governing the information supplied to users should provide a high degree of consumer protection, in order that medicinal products may be used correctly on the basis of full and comprehensible information.

(126) The marketing of medicinal products whose labelling and package leaflets comply with this Directive should not be prohibited or impeded on grounds connected with the labelling or package leaflet.

(127) The use of electronic and technological possibilities other than paper package leaflets can facilitate access to medicinal products, medicinal products distribution and should always guarantee equal or better quality of information to all patients compared to the paper form of product information.

(128) Member States have varying levels of digital literacy and internet access. In addition, patient and healthcare professional needs may differ. It is therefore necessary that Member States have a discretion on the adoption of measures enabling the electronic provision of product information while ensuring that no patient is left behind, taking into account the needs of different age categories and the different levels of digital literacy in the population, and making sure that product information is easily accessible to all patients. Member States should progressively allow the possibility for electronic product information, while ensuring full compliance with the rules on protection of personal data, and adhere to harmonised standards developed at EU level.

(129) Where Member States decide that the package leaflet should be made available in principle only electronically, they should also ensure that a paper version of the package leaflet is to be made available on demand and without additonal cost to patients. They should also ensure that the information in digital format is easily accessible to all patients, for instance by including in the outer packaging of the product a digitally readable barcode, which would direct the patient to the electronic version of the package leaflet.

(130) The use of multi-language packages can be a tool for access to medicinal products, in particular for small markets and in public health emergencies. Where multi-language packages are used, Member States may allow the use on the labelling and package leaflet of an official language of the Union that is commonly understood in the Member States where the multi-language package is marketed.

(131) To ensure a high level of transparency of public support to the research and development of medicinal products, the reporting of public contribution for the development of a particular medicinal product should be a requirement for all medicines. Given however the practical difficulty to identify how indirect public funding instruments, such as tax advantages, have supported a particular product, the reporting obligation should only concern the direct public financial support, such as direct grants or contracts. Therefore, the provisions of this Directive ensure, without prejudice to the rules on the protection of confidential and personal data, transparency regarding any direct financial support received from any public authority or public body to carry out any activities for the research and development of medicinal products.

(132) To ensure the accuracy of the information made publicly available by the marketing authorisation holder, the declared information has to be subject to audit by an independent auditor.

(133) In order to ensure a harmonised and consistent reporting of public contribution for the development of a particular medicinal products, the Commission should be able to adopt implementing acts to clarify the principles and format that the marketing authorisation holder should adhere to when reporting this information.

(134) This Directive is without prejudice to the application of measures adopted pursuant to Directive 2006/114/EC of the European Parliament and of the Council0 or pursuant to Directive 2005/29/EC of the European Parliament and of the Council0. Therefore the provisions regarding the advertising of medicinal products of this Directive should therefore be considered, where relevant, as a lex specialis with respect to Directive 2005/29/EC.

(135) Advertising, even of medicinal products not subject to a prescription, could affect public health and distort competition. Therefore, advertising of medicinal products should meet certain criteria. Persons qualified to prescribe, administer or supply medicinal products can properly evaluate the information available in advertising because of their knowledge, training and experience. The advertising of medicinal products to persons who cannot properly assess the risk associated with their use may lead to medicinal product misuse or overconsumption which is liable to harm public health. Therefore advertisement to the general public of medicinal products that are available only on medical prescription should be prohibited. Furthermore, distribution of samples free of charge to the general public for promotional ends is to be prohibited, also teleshopping for medicinal products shall be prohibited pursuant to Directive 2010/13/EU of the European Parliament and of the Council0. It should be possible within certain restrictive conditions to provide samples of medicinal products free of charge to persons qualified to prescribe or supply them so that they can familiarise themselves with new products and acquire experience in dealing with them.

(136) Advertising of medicinal products should aim at disseminating objective and unbiased information about the medicinal product. For that purpose, it is expressly forbidden highlight negatively another medicinal product or to suggest that advertised medicinal product might be safer or more effective than another medicinal product. Comparison of medicinal products should only be allowed if such information is listed in the summary of product characteristics of the medicinal product being advertised. This prohibition covers any medicinal product, also biosimilars, and therefore it would be misleading to refer in the advertising, that a biosimilar medicinal product would not be interchangeable with the original biological medicinal product or another biosimilar from the same original biological medicinal product. Additional strict rules about negative and comparative advertising of competitor medicinal products will prohibit claims that can mislead persons qualified to prescribe, administer or supply them.

(137) The dissemination of information which encourages the purchase of medicinal products should be considered within the concept of advertising of medicinal products, even where that information does not refer to a specific medicinal product, but to unspecified medicinal products.

(138) Advertising of medicinal products should be subject to strict conditions and effective, adequate monitoring. Reference in this regard should be made to the monitoring mechanisms set up by Directive 2006/114/EC.

(139) Medical sales representatives have an important role in the promotion of medicinal products. Therefore, certain obligations should be imposed upon them, in particular the obligation to supply the person visited with a summary of product characteristics.

(140) Innovative, ‘combination medicinal products’ and other developed medicinal products are complex in regards to their composition and administration. Therefore, in addition to persons qualified to prescribe medicinal products, also persons qualified to administer medicinal products need to be familiar with all characteristics of those medicinal products, especially with safe administration and use, including the comprehensive instructions to the patients. For that purpose information about medicinal products subject to medical prescription is also clearly allowed to persons qualified to administer them.

(141) Persons qualified to prescribe, administer or supply medicinal products should have access to a neutral, objective source of information about products available on the market. Whereas it is nevertheless for the Member States to take all measures necessary to this end, in the light of their own particular situation.

(142) In order to ensure that information on the use of the medicinal products in children are appropriately taken into account at the moment of marketing authorisation, it is therefore necessary to introduce a requirement for new medicinal products or when developing paediatric indications of already authorised products covered by a patent or a supplementary protection certificate, to present either the results of studies in the paediatric population in accordance with an agreed paediatric investigation plan or proof of having obtained a waiver or deferral, at the time of filing a marketing authorisation application or an application for a new therapeutic indication, new pharmaceutical form or new route of administration. In order to ensure that the data supporting the marketing authorisation concerning the use of a product in children, the competent authorities responsible for the authorisation of a medicinal product should check compliance with the agreed paediatric investigation plan and any waivers and deferrals at the validation step for marketing authorisation applications.

(143) 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, appropriate information should be included in the summary of product characteristics and, if appropriate, in the package leaflet. Information on waivers should also be included in product information. When all the measures in the paediatric investigation plan have been complied with, that fact should be recorded in the marketing authorisation, and that should then be the basis upon which companies can obtain rewards.

(144) Relevant data and information collected through clinical studies conducted before the introduction in the Union of a paediatric medicines Regulation and received by the competent authorities should be assessed without undue delay and taken into consideration for eventual variation of existing marketing authorisations.

(145) In order to ensure uniform conditions for the implementation of this Regulation, implementing powers should be conferred on the Commission. Those powers should be exercised in accordance with Regulation (EU) No 182/2011 of the European Parliament and of the Council0.

(146) Due to the need to reduce overall approval times for medicinal products, the time between the opinion of the Committee for Medicinal Products for Human Use (CHMP) and the final decision on any Commission Decision concerning national marketing authoristions, in particular for referrals, should be reduced to, in principle, 46 days.

(147) On the basis of the opinion of the Agency, the Commission should adopt a decision on the referral by means of implementing acts. In justified cases, the Commission may return the opinion for further examination or deviate in its decision from the opinion of the Agency. Taking into account the need to make medicinal products swiftly available to patients, it should be acknowledged that the chairperson of the Standing Committee for Medicines for Human Use will use the available mechanisms under Regulation 182/2011 and notably the possibility to obtain the committees opinion in written procedure and within expeditious deadlines which, in principle, will not exceed 10 calendar days.

(148) The Commission should be empowered to adopt any necessary changes to Annex II in order to take into account scientific and technical progress.

(149) In order to supplement or amend certain non-essential elements of this Directive, the power to adopt acts in accordance with Article 290 TFEU should be delegated to the Commission in respect of specifying the procedure for examination of application of active substance master file certificate, the publication of such certificates, the procedure for changes to the active substance master file and its certificate, access to the active substance master file and its assessment report; specifying additional quality master files to provide information on a constituent of a medicinal product, the procedure for examination of application of a quality master file certificate, the publication of such certificates, the procedure for changes to the quality master file and its certificate, and access to the quality master file and its assessment report; determining the situations in which post-authorisation efficacy studies may be required; specifying the categories of medicinal products to which a marketing authorisation subject to specific obligations could be granted and specifying the procedures and requirements for granting such a marketing authorisation and for its renewal; specifying exemptions to variation and the categories in which variations should be classified and establishing procedures for the examination of applications for variations to the terms of marketing authorisations as well as specifying conditions and procedures for cooperation with third countries and international organisations for examination of applications for such variations. It is of particular importance that the Commission carry out appropriate consultations during its preparatory work, including at expert level, and that those consultations be conducted in accordance with the principles laid down in the Interinstitutional Agreement of 13 April 2016 on Better Law-Making0. In particular, to ensure equal participation in the preparation of delegated acts, the European Parliament and the Council receive all documents at the same time as Member States’ experts, and their experts systematically have access to meetings of Commission expert groups dealing with the preparation of delegated acts.

(150) This Directive seeks to enable the right access to preventive healthcare and to benefit from medical treatment under the conditions established by national laws and practices and to ensure a high level of human health protection in the definition and implementation of all the Union’s policies and activities as laid down in Article 35 of the Charter of Fundamental Rights of the European Union.

(151) Since the objectives of this Directive, namely to establish rules on medicinal products ensuring the protection of public health and the environment as well as the functioning of the internal market, cannot be sufficiently achieved by the Member States as national rules would lead to disharmonisation, unequal patient access to medicinal products and barriers to the internal market, but can rather, by reason of its effects, be better achieved at Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of the Treaty on European Union. In accordance with the principle of proportionality, as set out in that Article, this Directive does not go beyond what is necessary in order to achieve those objectives.

(152) In accordance with the Joint Political Declaration of 28 September 2011 of Member States and the Commission on explanatory documents0, Member States have undertaken to accompany, in justified cases, the notification of their transposition measures with one or more documents explaining the relationship between the components of a directive and the corresponding parts of national transposition instruments. With regard to this Directive, the legislator considers the transmission of such documents to be justified.