Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use Text with EEA relevance

DIRECTIVE 2010/84/EU OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL

of 15 December 2010

amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use

(Text with EEA relevance)

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,

Having regard to the Treaty on the Functioning of the European Union, and in particular Article 114 and Article 168(4)(c) thereof,

Having regard to the proposal from the European Commission,

After transmission of the draft legislative act to the national parliaments,

Having regard to the opinion of the European Economic and Social Committee ([^E0001]),

Having regard to the opinion of the Committee of the Regions ([^E0002]),

Having regard to the opinion of the European Data Protection Supervisor ([^E0003]),

Acting in accordance with the ordinary legislative procedure ([^E0004]),

Whereas:

• (1) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use ([^E0005]) lays down harmonised rules for the authorisation, supervision and pharmacovigilance of medicinal products for human use within the Union.

• (2) 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.

• (3) In the light of the experience acquired and following an assessment by the Commission of the Union system of pharmacovigilance, it has become clear that it is necessary to take measures in order to improve the operation of Union law on the pharmacovigilance of medicinal products.

• (4) While the fundamental objective of the regulation of medicinal products is to safeguard public health, this aim should nevertheless be achieved by means that do not impede the free movement of safe medicinal products within the Union. It has emerged from the assessment of the Union system of pharmacovigilance that divergent actions by Member States in relation to safety issues pertaining to medicinal products are creating obstacles to the free movement of medicinal products. In order to prevent or eliminate those obstacles the existing pharmacovigilance provisions at Union level should be strengthened and rationalised.

• (5) For the sake of clarity, the definition of the term ‘adverse reaction’ should be amended to ensure that it covers noxious and unintended effects resulting not only from the authorised use of a medicinal product at normal doses, but also from medication errors and uses outside the terms of the marketing authorisation, including the misuse and abuse of the medicinal product. The suspicion of an adverse drug reaction, meaning that there is at least a reasonable possibility of there being a causal relationship between a medicinal product and an adverse event, should be sufficient reason for reporting. Therefore, the term ‘suspected adverse reaction’ should be used when referring to reporting obligations. Without prejudice to the existing Union and national provisions and practices on medical confidentiality, Member States should ensure that reporting and processing of personal data related to suspected adverse reactions, including those associated with medication errors is carried out on a confidential basis. This should not affect Member States’ obligations regarding the mutual exchange of information on pharmacovigilance issues or their obligation to make available to the public important information on pharmacovigilance concerns. Furthermore, the principle of confidentiality should not affect the obligations of the persons concerned to provide information under criminal law.

• (6) The pollution of waters and soils with pharmaceutical residues is an emerging environmental problem. Member States should consider measures to monitor and evaluate the risk of environmental effects of such medicinal products, including those which may have an impact on public health. The Commission should, based, inter alia, on data received from the European Medicines Agency, the European Environment Agency and Member States, produce a report on the scale of the problem, along with an assessment on whether amendments to Union legislation on medicinal products or other relevant Union legislation are required.

• (7) The marketing authorisation holder should establish a pharmacovigilance system to ensure the monitoring and supervision of one or more of its authorised medicinal products, recorded in a pharmacovigilance system master file which should be permanently available for inspection. The competent authorities should undertake to supervise those pharmacovigilance systems. Applications for marketing authorisations should therefore be accompanied by a brief description of the corresponding pharmacovigilance system, which should include a reference to the location where the pharmacovigilance system master file for the medicinal product concerned is kept and available for inspection by the competent authorities.

• (8) Marketing authorisation holders should plan pharmacovigilance measures for each individual medicinal product in the context of a risk management system. The measures should be proportionate to the identified risks, the potential risks, and the need for additional information on the medicinal product. It should also be ensured that any key measures included in a risk management system are made conditions of the marketing authorisation.

• (9) It is necessary from a public health perspective to complement the data available at the time of authorisation with additional data about the safety and, in certain cases, the efficacy of authorised medicinal products. Competent authorities should therefore be empowered to impose on the marketing authorisation holder the obligation to conduct post-authorisation studies on safety and on efficacy. It should be possible to impose that obligation at the time of the granting of the marketing authorisation or later, and it should be a condition of the marketing authorisation. Such studies may be aimed at collecting data to enable the assessment of the safety or efficacy of medicinal products in everyday medical practice.

• (10) It is essential that a strengthened system of pharmacovigilance not lead to the premature granting of marketing authorisations. However, some medicinal products are authorised subject to additional monitoring. This includes all medicinal products with a new active substance and biological medicinal products, including biosimilars, which are priorities for pharmacovigilance. Competent authorities may also require additional monitoring for specific medicinal products that are subject to the obligation to conduct a post-authorisation safety study or to conditions or restrictions with regard to the safe and effective use of the medicinal product. Medicinal products subject to additional monitoring should be identified as such by a black symbol and an appropriate standardised explanatory sentence in the summary of product characteristics and in the package leaflet. A publicly available list of medicinal products subject to additional monitoring should be kept up to date by the European Medicines Agency established by Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency ([^E0006]) (hereinafter referred to as the ‘Agency’).

• (11) The Commission should, in collaboration with the Agency and national competent authorities and following consultations with organisations representing patients, consumers, doctors and pharmacists, social health insurers, and other interested parties, present to the European Parliament and the Council an assessment report regarding the readability of the summaries of product characteristics and the package leaflets and their value to the healthcare professionals and the general public. Following an analysis of that data, the Commission should, if appropriate, make proposals to improve the layout and content of the summaries of product characteristics and of the package leaflets to ensure that they represent a valuable source of information for healthcare professionals and the general public respectively.

• (12) Experience has shown that the responsibilities of marketing authorisation holders with regard to pharmacovigilance of authorised medicinal products should be clarified. The marketing authorisation holder should be responsible for continuously monitoring the safety of its medicinal products, for informing the authorities of any changes that might impact on the marketing authorisation, and for ensuring that the product information is kept up to date. As medicinal products could be used outside the terms of the marketing authorisation, the marketing authorisation holder’s responsibilities should include providing all available information, including the results of clinical trials or other studies, as well as reporting any use of the medicinal product which is outside the terms of the marketing authorisation. It is also appropriate to ensure that all relevant information collected on the safety of the medicinal product is taken into account when the marketing authorisation is being renewed.

• (13) In order to ensure close cooperation between the Member States in the area of pharmacovigilance, the mandate of the coordination group set up by Article 27 of Directive 2001/83/EC should be enlarged to include the examination of questions related to the pharmacovigilance of all medicinal products authorised by the Member States. In order to fulfil its new tasks, the coordination group should be further strengthened through the adoption of clear rules as regards the expertise required, the procedures for reaching agreements or positions, transparency, independence and professional secrecy of its members, and the need for cooperation between Union and national bodies.

• (14) With a view to ensuring the same level of scientific expertise in the area of pharmacovigilance decision-making at both Union and national levels, the coordination group should rely on the recommendations of the Pharmacovigilance Risk Assessment Committee when fulfilling its pharmacovigilance tasks.

• (15) In order to avoid duplication of work, the coordination group should agree on a single position for pharmacovigilance assessments concerning medicinal products authorised in more than one Member State. Agreement within the coordination group should suffice for pharmacovigilance measures to be implemented throughout the Union. Where no agreement is reached within the coordination group, the Commission should be authorised to adopt a decision concerning the necessary regulatory action in respect of the marketing authorisation, addressed to the Member States.

• (16) A single assessment should also be conducted in the case of pharmacovigilance issues which concern medicinal products authorised by the Member States and medicinal products authorised in accordance with Regulation (EC) No 726/2004. In such cases, the Commission should adopt harmonised measures for all medicinal products concerned on the basis of an assessment at Union level.

• (17) Member States should operate a pharmacovigilance system to collect information that is useful for the monitoring of medicinal products, including information on suspected adverse reactions arising from use of a medicinal product within the terms of the marketing authorisation as well as from use outside the terms of the marketing authorisation, including overdose, misuse, abuse and medication errors, and suspected adverse reactions associated with occupational exposure. Member States should ensure the quality of the pharmacovigilance system through the follow-up of cases of suspected adverse reactions. For those tasks, Member States should establish a permanent pharmacovigilance system, supported by the appropriate expertise, so that the obligations under this Directive can be fully met.

• (18) In order to further increase the coordination of resources between the Member States, Member State should be authorised to delegate certain pharmacovigilance tasks to another Member State.

• (19) In order to simplify the reporting of suspected adverse reactions, the marketing authorisation holders and the Member States should report those reactions only to the Union pharmacovigilance database and data-processing network referred to in Article 57(1)(d) of Regulation (EC) No 726/2004 (the ‘Eudravigilance database’). The Eudravigilance database should be equipped to immediately forward reports on suspected adverse reactions received from marketing authorisation holders to the Member States on whose territory the reaction occurred.

• (20) In order to increase the level of transparency of the pharmacovigilance processes, the Member States should create and maintain medicines web-portals. To the same end, the marketing authorisation holders should provide the competent authorities with prior or simultaneous warnings about safety announcements and the competent authorities should also provide each other with advance notice of safety announcements.

• (21) Union rules in relation to pharmacovigilance should continue to rely on the crucial role of healthcare professionals in monitoring the safety of medicinal products, and should take account of the fact that patients are also well placed to report suspected adverse reactions to medicinal products. It is therefore appropriate to facilitate the reporting of suspected adverse reactions to medicinal products by both healthcare professionals and patients, and to make methods for such reporting available to them.

• (22) As a result of the submission of all suspected adverse reaction data directly to the Eudravigilance database, it is appropriate to amend the scope of periodic safety update reports so that they present an analysis of the risk-benefit balance of a medicinal product rather than a detailed listing of individual case reports already submitted to the Eudravigilance database.

• (23) Obligations imposed in respect of periodic safety update reports should be proportionate to the risks posed by medicinal products. Periodic safety update reporting should therefore be linked to the risk management system for newly authorised medicinal products and routine reporting should not be required for generic medicinal products, for medicinal products containing an active substance for which well-established medicinal use has been demonstrated, for homeopathic medicinal products or for traditional-use registered herbal medicinal products. However, in the interests of public health, the competent authorities should require periodic safety update reports for such medicinal products when concerns arise relating to pharmacovigilance data or as a result of the lack of available safety data when the use of the active substance concerned is concentrated in medicinal products for which periodic safety update reporting is not routinely required.

• (24) It is necessary to increase the shared use of resources between competent authorities for the assessment of periodic safety update reports. A single assessment of periodic safety update reports for medicinal products authorised in more than one Member State should be provided for. Moreover, procedures should be established to set single frequency and submission dates of periodic safety update reports for all medicinal products containing the same active substance or the same combination of active substances.

• (25) Following a single assessment of periodic safety update reports, any resulting measures as regards the maintenance, variation, suspension or revocation of the marketing authorisations concerned should be adopted through a Union procedure leading to a harmonised result.

• (26) The Member States should automatically submit certain safety issues related to medicinal products to the Agency thereby triggering a Union-wide assessment of the issue. Therefore it is appropriate to establish rules for an assessment procedure by the Pharmacovigilance Risk Assessment Committee, and for the subsequent follow-up as regards the marketing authorisations concerned with a view to the adoption of harmonised measures across the Union.

• (27) In connection with the clarification and strengthening of the provisions relating to pharmacovigilance activities in Directive 2001/83/EC, it is also appropriate to further clarify the procedures for all Union-wide post-authorisation assessments of safety issues concerning medicinal products. To that end, the number of procedures for Union-wide assessment should be limited to two, one of which allows for a swift assessment and should be applied when urgent action is considered necessary. Regardless of whether the urgent procedure or the normal procedure is applied, and whether the medicinal product was authorised through the centralised or non-centralised procedure, the Pharmacovigilance Risk Assessment Committee should always give its recommendation when the reason for taking action is based on pharmacovigilance data. It is appropriate that the coordination group and the Committee for Medicinal Products for Human Use should rely on this recommendation when performing their assessment of the issue.

• (28) It is necessary to introduce harmonised guiding principles for, and regulatory supervision of, post-authorisation safety studies that are requested by competent authorities and that are non-interventional, that are initiated, managed or financed by the marketing authorisation holder, and that involve the collection of data from patients or healthcare professionals and that therefore fall outside of the scope of Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use ([^E0007]). The supervision of such studies should be the responsibility of the Pharmacovigilance Risk Assessment Committee. Studies requested after the marketing authorisation of a medicinal product by only one competent authority to be conducted in only one Member State should be supervised by the national competent authority of the Member State in which the study is to be conducted. Provision should also be made for the subsequent follow-up, if appropriate, as regards the marketing authorisations concerned with a view to the adoption of harmonised measures across the Union.

• (29) In order to enforce the provisions relating to pharmacovigilance, the Member States should ensure that effective, proportionate and dissuasive penalties are applied to marketing authorisation holders for non-compliance with pharmacovigilance obligations. If the conditions included in the marketing authorisation are not fulfilled within the given deadline, the national competent authorities should have the power to review the marketing authorisation.

• (30) In order to protect public health, the pharmacovigilance activities of national competent authorities should be adequately funded. It should be ensured that adequate funding is possible for pharmacovigilance activities by empowering the national competent authorities to charge fees to marketing authorisation holders. However, the management of those collected funds should be under the permanent control of the national competent authorities in order to guarantee their independence in the performance of those pharmacovigilance activities.

• (31) It should be possible for Member States to allow the relevant actors, under certain conditions, to deviate from certain provisions of Directive 2001/83/EC related to the requirements for labelling and packaging in order to address severe availability problems related to the potential lack of authorised medicinal products or of medicinal products placed on the market or shortages thereof.

• (32) Since the objective of this Directive, namely to improve the safety of medicinal products placed on the market in the Union in a harmonised way across the Member States, cannot be sufficiently achieved by the Member States and can, by reason of the scale of the measures, 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 (TEU). 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 this objective.

• (33) This Directive shall apply without prejudice to Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data ([^E0008]) and Regulation (EC) No 45/2001 of the European Parliament and of the Council of 18 December 2000 on the protection of individuals with regard to the processing of personal data by the Community institutions and bodies and on the free movement of such data ([^E0009]). In order to detect, assess, understand and prevent adverse reactions, and to identify and take actions to reduce the risks of, and increase the benefits from, medicinal products for the purpose of safeguarding public health, it should be possible to process personal data within the Eudravigilance system while respecting Union legislation relating to data protection. The purpose of safeguarding public health constitutes a substantial public interest and consequently the processing of personal data can be justified if identifiable health data are processed only when necessary and only when the parties involved assess this necessity at every stage of the pharmacovigilance process.

• (34) The provisions on the monitoring of medicinal products in Directive 2001/83/EC constitute specific provisions within the meaning of Article 15(2) of Regulation (EC) No 765/2008 of the European Parliament and of the Council of 9 July 2008 setting out the requirements for accreditation and market surveillance relating to the marketing of products ([^E0010]).

• (35) The pharmacovigilance activities provided for in this Directive require that uniform conditions be established as concerns the contents and maintenance of the pharmacovigilance system master file, as well as the minimum requirements for the quality system for the performance of pharmacovigilance activities by the national competent authorities and marketing authorisation holders, the use of internationally agreed terminology, formats and standards for the performance of pharmacovigilance activities, and the minimum requirements for the monitoring of the data contained in the Eudravigilance database to determine whether there are new risks or whether risks have changed. The format and content of the electronic transmission of suspected adverse reactions by Member States and marketing authorisation holders, the format and content of electronic periodic safety update reports and risk management plans as well as the format of protocols, abstracts and final study reports for the post-authorisation safety studies should also be established. In accordance with Article 291 of the Treaty on the Functioning of the European Union (TFEU), rules and general principles concerning mechanisms for the control by Member States of the Commission’s exercise of implementing powers are to be laid down in advance by a regulation adopted in accordance with the ordinary legislative procedure. Pending the adoption of that new regulation, Council Decision 1999/468/EC of 28 June 1999 laying down the procedures for the exercise of implementing powers conferred on the Commission ([^E0011]) continues to apply, with the exception of the regulatory procedure with scrutiny, which is not applicable.

• (36) The Commission should be empowered to adopt delegated acts in accordance with Article 290 TFEU in order to supplement the provisions in Articles 21a and 22a of Directive 2001/83/EC. The Commission should be empowered to adopt supplementary measures laying down the situations in which post-authorisation efficacy studies may be required. It is of particular importance that the Commission carry out appropriate consultations during its preparatory work, including at expert level.

• (37) In accordance with point 34 of the Interinstitutional Agreement on better law-making ([^E0012]), Member States are encouraged to draw up, for themselves and in the interests of the Union, their own tables illustrating, as far as possible, the correlation between this Directive and the transposition measures, and to make them public.

• (38) Directive 2001/83/EC should be amended accordingly,

HAVE ADOPTED THIS DIRECTIVE:

Article 1

Amendments to Directive 2001/83/EC

Directive 2001/83/EC is hereby amended as follows:

• 1.Article 1 is amended as follows: (a)point 11 is replaced by the following: ‘11. Adverse reaction : A response to a medicinal product which is noxious and unintended.’; (b)point 14 is deleted; (c)point 15 is replaced by the following: ‘15. Post-authorisation safety study : Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures.’; (d)the following points are inserted: ‘28b. Risk management system : a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to a medicinal product, including the assessment of the effectiveness of those activities and interventions. 28c. Risk management plan : a detailed description of the risk management system. 28d. Pharmacovigilance system : a system used by the marketing authorisation holder and by Member States to fulfil the tasks and responsibilities listed in Title IX and designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance. 28e. Pharmacovigilance system master file : A detailed description of the pharmacovigilance system used by the marketing authorisation holder with respect to one or more authorised medicinal products.’.

• 2.Article 8(3) is amended as follows: (a)point (ia) is replaced by the following: ‘(ia)A summary of the applicant’s pharmacovigilance system which shall include the following elements: —proof that the applicant has at his disposal a qualified person responsible for pharmacovigilance, —the Member States in which the qualified person resides and carries out his/her tasks, —the contact details of the qualified person, —a statement signed by the applicant to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX, —a reference to the location where the pharmacovigilance system master file for the medicinal product is kept.’, (b)the following point is inserted after point (ia): ‘(iaa)The risk management plan describing the risk management system which the applicant will introduce for the medicinal product concerned, together with a summary thereof.’; (c)point (l) is replaced by the following: ‘(l)Copies of the following: —any authorisation, obtained in another Member State or in a third country, to place the medicinal product on the market, a summary of the safety data including the data contained in the periodic safety update reports, where available, and suspected adverse reactions reports, together with a list of those Member States in which an application for authorisation submitted in accordance with this Directive is under examination; —the summary of the product characteristics proposed by the applicant in accordance with Article 11 or approved by the competent authorities of the Member State in accordance with Article 21 and the package leaflet proposed in accordance with Article 59 or approved by the competent authorities of the Member State in accordance with Article 61; —details of any decision to refuse authorisation, whether in the Union or in a third country, and the reasons for such a decision.’, (d)point (n) is deleted; (e)the following subparagraphs are added after the second subparagraph: ‘The risk management system referred to in point (iaa) of the first subparagraph shall be proportionate to the identified risks and the potential risks of the medicinal product, and the need for post-authorisation safety data. The information referred to in the first subparagraph shall be updated where and when appropriate.’.

• 3.In Article 11 the following subparagraphs are added: ‘For medicinal products included on the list referred to in Article 23 of Regulation (EC) No 726/2004, the summary of product characteristics shall include the statement: “This medicinal product is subject to additional monitoring”. This statement shall be preceded by the black symbol referred to in Article 23 of Regulation (EC) No 726/2004 and followed by an appropriate standardised explanatory sentence. For all medicinal products, a standard text shall be included expressly asking healthcare professionals to report any suspected adverse reaction in accordance with the national spontaneous reporting system referred to in Article 107a(1). Different ways of reporting, including electronic reporting, shall be available in compliance with the second subparagraph of Article 107a(1).’.

• 4.Article 16g(1) is replaced by the following: ‘1.  Article 3(1) and (2), Article 4(4), Article 6(1), Article 12, Article 17(1), Articles 19, 20, 23, 24, 25, 40 to 52, 70 to 85, 101 to 108b, Article 111(1) and (3), Articles 112, 116, 117, 118, 122, 123, 125, the second paragraph of Article 126, and Article 127 of this Directive as well as Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use ([^E0013]) shall apply, by analogy, to traditional-use registration granted under this Chapter.

• 5.Article 17 is amended as follows: (a)in the second subparagraph of paragraph 1, the words ‘Articles 27’ are replaced by the words ‘Articles 28’; (b)in paragraph 2, the words ‘Articles 27’ are replaced by the words ‘Articles 28’;

• 6.In Article 18, the words ‘Articles 27’ are replaced by the words ‘Articles 28’.

• 7.In Article 21, paragraphs 3 and 4 are replaced by the following: ‘3.  The national competent authorities shall, without delay, make publicly available the marketing authorisation together with the package leaflet, the summary of the product characteristics and any conditions established in accordance with Articles 21a, 22 and 22a, together with any deadlines for the fulfilment of those conditions for each medicinal product which they have authorised.

The national competent authorities shall make the assessment report publicly accessible without delay, together with the reasons for their opinion, after deletion of any information of a commercially confidential nature. The justification shall be provided separately for each indication applied for. The public assessment report shall include a summary written in a manner that is understandable to the public. The summary shall contain, in particular, a section relating to the conditions of use of the medicinal product.’.

• 8.The following Article is inserted: ‘Article 21a In addition to the provisions laid down in Article 19, a marketing authorisation for a medicinal product may be granted subject to one or more of the following conditions: (a)to take certain measures for ensuring the safe use of the medicinal product to be included in the risk management system; (b)to conduct post-authorisation safety studies; (c)to comply with obligations on the recording or reporting of suspected adverse reactions which are stricter than those referred to in Title IX; (d)any other conditions or restrictions with regard to the safe and effective use of the medicinal product; (e)the existence of an adequate pharmacovigilance system; (f)to conduct post-authorisation efficacy studies where concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed. Such an obligation to conduct such studies shall be based on the delegated acts adopted pursuant to Article 22b while taking into account the scientific guidance referred to in Article 108a. The marketing authorisation shall lay down deadlines for the fulfilment of these conditions where necessary.’.

• 9.Article 22 is replaced by the following: ‘Article 22 In exceptional circumstances and following consultation with the applicant, the marketing authorisation may be granted subject to certain conditions, in particular relating to the safety of the medicinal product, notification to the national competent authorities of any incident relating to its use, and action to be taken. The marketing authorisation may be granted only when the applicant can show that he is unable to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use, for objective, verifiable reasons and must be based on one of the grounds set out in Annex I. Continuation of the marketing authorisation shall be linked to the annual reassessment of these conditions.’.

• 10.The following Articles are inserted: ‘Article 22a

(a)to conduct a post-authorisation safety study if there are concerns about the risks of an authorised medicinal product. If the same concerns apply to more than one medicinal product, the national competent authority shall, following consultation with the Pharmacovigilance Risk Assessment Committee, encourage the marketing authorisation holders concerned to conduct a joint post-authorisation safety study; (b)to conduct a post-authorisation efficacy study when the understanding of the disease or the clinical methodology indicate that previous efficacy evaluations might have to be revised significantly. The obligation to conduct the post-authorisation efficacy study shall be based on the delegated acts adopted pursuant to Article 22b while taking into account the scientific guidance referred to in Article 108a. The imposition of such an obligation shall be duly justified, notified in writing, and shall include the objectives and timeframe for submission and conduct of the study.

Article 22b

Article 22c

• 11.Article 23 is replaced by the following: ‘Article 23

Those changes shall be subject to the approval of the competent authority of the Member State concerned.

In particular, the marketing authorisation holder shall forthwith inform the national competent authority of any prohibition or restriction imposed by the competent authorities of any country in which the medicinal product is marketed and of any other new information which might influence the evaluation of the benefits and risks of the medicinal product concerned. The information shall include both positive and negative results of clinical trials or other studies in all indications and populations, whether or not included in the marketing authorisation, as well as data on the use of the medicinal product where such use is outside the terms of the marketing authorisation.

The national competent authority may at any time ask the marketing authorisation holder to submit a copy of the pharmacovigilance system master file. The marketing authorisation holder shall submit the copy at the latest 7 days after receipt of the request.’.

• 12.Article 24 is amended as follows: (a)in paragraph 2, the second subparagraph is replaced by the following: ‘To this end, the marketing authorisation holder shall provide the national competent authority with a consolidated version of the file in respect of quality, safety and efficacy, including the evaluation of data contained in suspected adverse reactions reports and periodic safety update reports submitted in accordance with Title IX, and information on all variations introduced since the marketing authorisation was granted, at least 9 months before the marketing authorisation ceases to be valid in accordance with paragraph 1.’; (b)paragraph 3 is replaced by the following: ‘3.  Once renewed, the marketing authorisation shall be valid for an unlimited period, unless the national competent authority decides, on justified grounds relating to pharmacovigilance, including exposure of an insufficient number of patients to the medicinal product concerned, to proceed with one additional five-year renewal in accordance with paragraph 2.’.

• 13.The title ‘Chapter 4 Mutual recognition and decentralised procedure’ is deleted.

• 14.Article 27 is amended as follows: (a)paragraphs 1 and 2 are replaced by the following: ‘1.  A coordination group shall be set up for the following purposes: (a)the examination of any question relating to a marketing authorisation of a medicinal product in two or more Member States in accordance with the procedures laid down in Chapter 4; (b)the examination of questions related to the pharmacovigilance of medicinal products authorised by the Member States, in accordance with Articles 107c, 107e, 107g, 107k and 107q; (c)the examination of questions relating to variations of marketing authorisations granted by the Member States, in accordance with Article 35(1). The Agency shall provide the secretariat of this coordination group. For the fulfilment of its pharmacovigilance tasks, including approving risk management systems and monitoring their effectiveness, the coordination group shall rely on the scientific assessment and the recommendations of the Pharmacovigilance Risk Assessment Committee provided for in Article 56(1)(aa) of Regulation (EC) No 726/2004.

Members of the coordination group and experts shall, for the fulfilment of their tasks, rely on the scientific and regulatory resources available to national competent authorities. Each national competent authority shall monitor the level of expertise of the evaluations carried out and facilitate the activities of nominated coordination group members and experts.

Article 63 of Regulation (EC) No 726/2004 shall apply to the coordination group as regards transparency and the independence of its members.’;

(b)the following paragraphs are added: ‘4.  The Executive Director of the Agency or his representative and representatives of the Commission shall be entitled to attend all meetings of the coordination group.

• 15.After Article 27 the following heading is inserted: ‘CHAPTER 4 Mutual recognition and decentralised procedure’.

• 16.Article 31(1) is amended as follows: (a)the first subparagraph is replaced by the following: ‘The Member States, the Commission, the applicant or the marketing authorisation holder shall, in specific cases where the interests of the Union are involved, refer the matter to the Committee for application of the procedure laid down in Articles 32, 33 and 34 before any decision is reached on an application for a marketing authorisation or on the suspension or revocation of a marketing authorisation, or on any other variation of the marketing authorisation which appears necessary.’; (b)the following subparagraphs are inserted after the first subparagraph: ‘Where the referral results from the evaluation of data relating to pharmacovigilance of an authorised medicinal product, the matter shall be referred to the Pharmacovigilance Risk Assessment Committee and Article 107j(2) may be applied. The Pharmacovigilance Risk Assessment Committee shall issue a recommendation according to the procedure laid down in Article 32. The final recommendation shall be forwarded to the Committee for Medicinal Products for Human Use or to the coordination group, as appropriate, and the procedure laid down in Article 107k shall apply. However, where urgent action is considered necessary, the procedure laid down in Articles 107i to 107k shall apply.’.

• 17.Article 36 is deleted.

• 18.Article 59 is amended as follows: (a)paragraph 1 is amended as follows: (i)point (e) is replaced by: ‘(e)a description of the adverse reactions which may occur under normal use of the medicinal product and, if necessary, the action to be taken in such a case.’; (ii)the following subparagraphs are added: ‘For medicinal products included in the list referred to in Article 23 of Regulation (EC) No 726/2004, the following additional statement shall be included “This medicinal product is subject to additional monitoring”. This statement shall be preceded by the black symbol referred to in Article 23 of Regulation (EC) No 726/2004 and followed by an appropriate standardised explanatory sentence. For all medicinal products, a standardised text shall be included, expressly asking patients to communicate any suspected adverse reaction to his/her doctor, pharmacist, healthcare professional or directly to the national spontaneous reporting system referred to in Article 107a(1), and specifying the different ways of reporting available (electronic reporting, postal address and/or others) in compliance with the second subparagraph of Article 107a(1).’; (b)the following paragraph is added: ‘4.  By 1 January 2013, the Commission shall present to the European Parliament and the Council an assessment report on current shortcomings in the summary of product characteristics and the package leaflet and how they could be improved in order to better meet the needs of patients and healthcare professionals. The Commission shall, if appropriate, and on the basis of the report, and consultation with appropriate stakeholders, present proposals in order to improve the readability, layout and content of these documents. ’

• 19.Article 63(3) is replaced by the following: ‘3.  When the medicinal product is not intended to be delivered directly to the patient, or where there are severe problems in respect of the availability of the medicinal product, the competent authorities may, subject to measures they consider necessary to safeguard human health, grant an exemption to the obligation that certain particulars should appear on the labelling and in the package leaflet. They may also grant a full or partial exemption to the obligation that the labelling and the package leaflet must be in the official language or languages of the Member State in which the medicinal product is placed on the market.’.

• 20.Title IX is replaced by the following: ‘TITLE IX PHARMACOVIGILANCE

CHAPTER 1 General provisions

Article 101

The pharmacovigilance system shall be used to collect information on the risks of medicinal products as regards patients’ or public health. That information shall in particular refer to adverse reactions in human beings, arising from use of the medicinal product within the terms of the marketing authorisation as well as from use outside the terms of the marketing authorisation, and to adverse reactions associated with occupational exposure.

Article 102

The Member States shall: (a)take all appropriate measures to encourage patients, doctors, pharmacists and other healthcare professionals to report suspected adverse reactions to the national competent authority; for these tasks, organisations representing consumers, patients and healthcare professionals may be involved as appropriate; (b)facilitate patient reporting through the provision of alternative reporting formats in addition to web-based formats; (c)take all appropriate measures to obtain accurate and verifiable data for the scientific evaluation of suspected adverse reaction reports; (d)ensure that the public is given important information on pharmacovigilance concerns relating to the use of a medicinal product in a timely manner through publication on the web-portal and through other means of publicly available information as necessary; (e)ensure, through the methods for collecting information and where necessary through the follow-up of suspected adverse reaction reports, that all appropriate measures are taken to identify clearly any biological medicinal product prescribed, dispensed, or sold in their territory which is the subject of a suspected adverse reaction report, with due regard to the name of the medicinal product, in accordance with Article 1(20), and the batch number; (f)take the necessary measures to ensure that a marketing authorisation holder who fails to discharge the obligations laid down in this Title is subject to effective, proportionate and dissuasive penalties. For the purposes of point (a) and (e) of the first paragraph the Member States may impose specific obligations on doctors, pharmacists and other health-care professionals.

Article 103

A Member State may delegate any of the tasks entrusted to it under this Title to another Member State subject to a written agreement of the latter. Each Member State may represent no more than one other Member State. The delegating Member State shall inform the Commission, the Agency and all other Member States of the delegation in writing. The delegating Member State and the Agency shall make that information public.

Article 104

The marketing authorisation holder shall perform a regular audit of his pharmacovigilance system. He shall place a note concerning the main findings of the audit on the pharmacovigilance system master file and, based on the audit findings, ensure that an appropriate corrective action plan is prepared and implemented. Once the corrective actions have been fully implemented, the note may be removed.

(a)have permanently and continuously at his disposal an appropriately qualified person responsible for pharmacovigilance; (b)maintain and make available on request a pharmacovigilance system master file; (c)operate a risk management system for each medicinal product; (d)monitor the outcome of risk minimisation measures which are contained in the risk management plan or which are laid down as conditions of the marketing authorisation pursuant to Articles 21a, 22 or 22a; (e)update the risk management system and monitor pharmacovigilance data to determine whether there are new risks or whether risks have changed or whether there are changes to the benefit-risk balance of medicinal products. The qualified person referred to in point (a) of the first subparagraph shall reside and operate in the Union and shall be responsible for the establishment and maintenance of the pharmacovigilance system. The marketing authorisation holder shall submit the name and contact details of the qualified person to the competent authority and the Agency.

Article 104a

The imposition of such obligations shall be duly justified, notified in writing and shall include the timeframe for submission of the detailed description of the risk-management system.

Article 105

The management of funds intended for activities connected with pharmacovigilance, the operation of communication networks and market surveillance shall be under the permanent control of the national competent authorities in order to guarantee their independence in the performance of those pharmacovigilance activities. The first paragraph shall not preclude the national competent authorities from charging fees to marketing authorisation holders for performing those activities by the national competent authorities on the condition that their independence in the performance of those pharmacovigilance activities is strictly guaranteed.

CHAPTER 2 Transparency and communications

Article 106

Each Member State shall set up and maintain a national medicines web-portal which shall be linked to the European medicines web-portal established in accordance with Article 26 of Regulation (EC) No 726/2004. By means of the national medicines web-portals, the Member States shall make publicly available at least the following: (a)public assessment reports, together with a summary thereof; (b)summaries of product characteristics and package leaflets; (c)summaries of risk management plans for medicinal products authorised in accordance with this Directive; (d)the list of medicinal products referred to in Article 23 of Regulation (EC) No 726/2004; (e)information on the different ways of reporting suspected adverse reactions to medicinal products to national competent authorities by healthcare professionals and patients, including the web-based structured forms referred to in Article 25 of Regulation (EC) No 726/2004.

Article 106a

The marketing authorisation holder shall ensure that information to the public is presented objectively and is not misleading.

Under the coordination of the Agency, the Member States shall make all reasonable efforts to agree on a common message in relation to the safety of the medicinal product concerned and the timetables for their distribution. The Pharmacovigilance Risk Assessment Committee shall, at the request of the Agency, provide advice on those safety announcements.

CHAPTER 3 Recording, reporting and assessment of pharmacovigilance data

Section 1 Recording and reporting of suspected adverse reactions

Article 107

Marketing authorisation holders shall ensure that those reports are accessible at a single point within the Union. By way of derogation from the first subparagraph, suspected adverse reactions occurring in the context of a clinical trial shall be recorded and reported in accordance with Directive 2001/20/EC.

Marketing authorisation holders shall submit electronically to the Eudravigilance database information on all non-serious suspected adverse reactions that occur in the Union, within 90 days following the day on which the marketing authorisation holder concerned gained knowledge of the event. For medicinal products containing the active substances referred to in the list of publications monitored by the Agency pursuant to Article 27 of Regulation (EC) No 726/2004, marketing authorisation holders shall not be required to report to the Eudravigilance database the suspected adverse reactions recorded in the listed medical literature, but they shall monitor all other medical literature and report any suspected adverse reactions.

Article 107a

Member States shall ensure that reports of such reactions may be submitted by means of the national medicines web-portals or by other means.

They shall, within 90 days from the receipt of reports referred to in paragraph 1, submit reports of non-serious suspected adverse reactions electronically to the Eudravigilance database. Marketing authorisation holders shall access those reports through the Eudravigilance database.

Section 2 Periodic safety update reports

Article 107b

(a)summaries of data relevant to the benefits and risks of the medicinal product, including results of all studies with a consideration of their potential impact on the marketing authorisation; (b)a scientific evaluation of the risk-benefit balance of the medicinal product; (c)all data relating to the volume of sales of the medicinal product and any data in possession of the marketing authorisation holder relating to the volume of prescriptions, including an estimate of the population exposed to the medicinal product. The evaluation referred to in point (b) shall be based on all available data, including data from clinical trials in unauthorised indications and populations. The periodic safety update reports shall be submitted electronically.

(a)where such obligation has been laid down as a condition in the marketing authorisation in accordance with Article 21a or Article 22; or (b)when requested by a competent authority on the basis of concerns relating to pharmacovigilance data or due to the lack of periodic safety update reports relating to an active substance after the marketing authorisation has been granted. The assessment reports of the requested periodic safety update reports shall be communicated to the Pharmacovigilance Risk Assessment Committee, which shall consider whether there is a need for a single assessment report for all marketing authorisations for medicinal products containing the same active substance and inform the coordination group or the Committee for Medicinal Products for Human Use accordingly, in order to apply the procedures laid down in Article 107c(4) and Article 107e.

Article 107c

The dates of submission according to the specified frequency shall be calculated from the date of the authorisation.

Periodic safety update reports shall be submitted to the competent authorities immediately upon request or in accordance with the following: (a)where a medicinal product has not yet been placed on the market, at least every 6 months following authorisation and until the placing on the market; (b)where a medicinal product has been placed on the market, at least every 6 months during the first 2 years following the initial placing on the market, once a year for the following 2 years and at three-yearly intervals thereafter.

This harmonised frequency for the submission of the reports and the Union reference date may be determined, after consultation of the Pharmacovigilance Risk Assessment Committee, by one of the following: (a)the Committee for Medicinal Products for Human Use, where at least one of the marketing authorisations for the medicinal products containing the active substance concerned has been granted in accordance with the centralised procedure provided for in Chapter 1 of Title II of Regulation (EC) No 726/2004; (b)the coordination group, in other cases than those referred to in point (a). The harmonised frequency for the submission of the reports determined pursuant to the first and second subparagraphs shall be made public by the Agency. Marketing authorisation holders shall submit an application for a variation of the marketing authorisation accordingly.

(a)the date of the first marketing authorisation in the Union of a medicinal product containing that active substance or that combination active substances; (b)if the date referred to in point (a) cannot be ascertained, the earliest of the known dates of the marketing authorisations for a medicinal product containing that active substance or that combination of active substances.