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 (5) 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 (6) (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 (7). 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 (8) 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 (9). 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 (10).
(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 (11) 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 (12), 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,
