Explanatory Memorandum to COM(2008)664 - Proposal for a Regulation of the European Parliament and of the Council amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency - Main contents
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| dossier | COM(2008)664 - Proposal for a Regulation of the European Parliament and of the Council amending, as regards pharmacovigilance of medicinal ... |
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| source | COM(2008)664  |
| date | 10-12-2008 |
Medicinal products contribute considerably to the health of EU citizens. The discovery, development and effective use of medicinal products improve quality of life, reduce the length of time spent in hospital and save lives. Medicinal products can, however, also have adverse effects and adverse drug reactions present an important public health burden in the Community. It is estimated that 5% of all hospital admissions are due to an adverse drug reaction, 5% of all hospital patients suffer an adverse drug reaction and adverse drug reactions are the fifth most common cause of hospital death.
Some adverse reactions will only be detected after a medicine has been authorised and the full safety profile of medicinal products can only be known once they have entered the market. Pharmacovigilance rules are therefore necessary for the protection of public health in order to prevent, detect and assess adverse effects of medicinal products.
Community rules so far adopted have made a major contribution to the achievement of the objective that medicinal products authorised to be placed on the Community market are continuously monitored as regards their safety. However, in the light of the experience acquired and following an assessment by the Commission of the Community system of pharmacovigilance, it has become clear that new measures are necessary to improve the operation of the Community rules on the pharmacovigilance of medicinal products for human use.
Therefore, the proposals aim at the strengthening and rationalizing the Community pharmacovigilance system of medicinal products for human use through the amendment of the two legal acts governing this field, with the overall objectives of better protecting public health, ensuring proper functioning of the internal market. and simplifying the current rules and procedures. The specific objectives are:
- Providing for clear roles and responsibilities for the key responsible parties and clear obligations against which they perform their roles;
- Rationalising EU decision-making on drug safety issues in order to deliver measures that are equally and fully implemented for all relevant products and across the Community with a view to preventing unnecessary patient exposure to risks;
- Strengthening medicines safety transparency and communication to increase the understanding and trust of patients and health professionals in the safety of medicines and improve the penetration of key warnings;
- Strengthening companies' pharmacovigilance systems, allowing companies to improve their systems constantly while reducing administrative burden;
- Ensuring the proactive and proportionate collection of high quality data relevant to the safety of medicines through risk management and structured data collection in the form of post authorisation safety studies, together with rationalised single case and periodic reporting of suspected adverse reactions;
- Involving stakeholders in pharmacovigilance including through direct patient reporting of suspected adverse reactions and inclusion of patients and heath-care professionals in decision-making.
- Simplification of the current Community pharmacovigilance procedures with consequent efficiency gains for both the pharmaceutical industry and medicines regulators.
Pharmacovigilance is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects of medicinal products.
The Community has had legislation on medicinal products on pharmacovigilance since 1965. Until now there has been no systematic review of the Community pharmacovigilance legislation, its operation and its effect on protecting public health. Therefore, in 2004 the Commission services launched an independent study into the functioning of the Community pharmacovigilance system. The independent report together with a subsequent broad public consultation revealed several shortcomings.
Harmonised Community rules on the pharmacovigilance of medicinal products for human use are laid down in:
- 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 i, as regards medicinal products authorized by the Commission in accordance with the procedure of that Regulation (the so-called 'centralised procedure'); and
- 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 i, as regards general rules on medicinal products for human use and specific rules for medicinal products authorised by the Member States.
While the rules are broadly the same in substance, there are certain divergences and various provisions are duplicated in the two legal texts. It is appropriate to rationalise and simplify this by laying down all general rules in the Community code on medicinal products for human use (Directive 2001/83/EC), and cross-referring to them in the regulation governing the centralised procedure (Regulation (EC) No 726/2004), with specific provisions for centrally authorised products only when justified.
The proposals are consistent with the overall objective of the Community legislation on medicinal products for human use, which is to remove disparities between national provisions in order to ensure the proper functioning of the internal market for such products, while at the same time safeguarding a high level of protection of public and human health. They are also consistent with Article 152 i of the Treaty establishing the European Community, which provides that a high level of human health protection shall be ensured in the definition and implementation of all Community policies and activities.
The proposal is equally consistent with the Commission patient safety initiative i and the Commission work to stimulate innovation in the pharmaceutical sector, through the 7th Framework programme in general and the Innovative Medicines Initiative i in particular. The proposal is also consistent with Community projects which aim to develop and validate the use of innovative information technology tools to identify medicines adverse events i.
All interested parties, in particular patient and healthcare professionals, Member States competent authorities and industry, have been widely consulted on this proposal. Various means of consultation have been used, namely two internet-based public consultations, dedicated workshops, questionnaires and bilateral meetings.
Additional information on the consultations conducted can be found in the Impact Assessment attached to this proposal. The detailed results of both parts of the consultation, including the individual consultation responses can be found at: ec.europa.eu/enterprise/pharmaceuticals
The details of the impact assessment are provided in the Commission Staff Working Document Impact Assessment attached to this proposal.
In conclusion, the impact assessment suggests that increasing the clarity, efficiency and quality of the EU system of pharmacovigilance, through amendments to the existing Community legal framework, leads to major public health improvements and overall cost savings to the EU industry sector.
Contents
- Legal elements of the proposal
- Budgetary implication
- 1.1. Grounds for and objectives of the proposal
- 1.2. General context
- 1.3. Existing provisions in the area of the proposal
- 1.4. Consistency with the other policies and objectives of the Union
- 2. CONSULTATION OF INTERESTED PARTIES AND IMPACT ASSESSMENT
- 2.1. Consultation of interested parties
- 2.2. Impact assessment
- 3.1. Summary of the proposed action
- Clear roles and responsibilities
- Transparency and communication
- Pharmacovigilance obligations by the marketing authorisation holder
- Risk management planning and non-interventional safety studies
- Adverse drug reaction case reports
- Periodic safety update reports and other safety related assessments
- 3.2. Legal basis
- 3.3. Subsidiarity principle
- 3.4. Proportionality principle
- 3.5. Choice of instruments
- 5. Additional information
- 5.1. Simplification
- 5.2. European Economic Area
The key elements of the proposals can be summarised as follows:
Current legislation contains some instances of overlapping or ambiguous responsibilities for pharmacovigilance.
The tasks and responsibilities of involved parties in the legislation (Member State, Agency, marketing authorisation holders) are clarified and codified and the concept and scope of Good Vigilance Practices for all involved in pharmacovigilance is established. The key tasks of the Agency in the area of pharmacovigilance laid down in Regulation (EC) No 726/2004 are overall maintained, but the Agency's coordinating role at the centre of the Community pharmacovigilance system is reinforced. The Member States should remain core to the operation of pharmacovigilance in the Community, with increased cooperation and work-sharing mechanisms. The pharmacovigilance responsibilities of marketing authorisation holders are also clarified, in particular as regards the scope of the obligation of marketing authorisation holders to continuously monitor the safety of products to ensure that all information available is brought to the attention of the authorities.
A new scientific committee responsible for pharmacovigilance is created within the Agency, the Pharmacovigilance Risk Assessment Advisory Committee. The Committee is intended to play a key role in the pharmacovigilance assessments in the Community, by providing support both to the Committee for Medicinal Products for Human Use within the Agency (responsible for opinions on the quality, safety and efficacy of medicinal products for human use in the framework of Community procedures), and the coordination group of Member States established by Directive 2001/83/EC (involved in the national authorisation procedures).
The mandate of the coordination group composed of Member States representatives set up by Article 27 of Directive 2001/83/EC is enhanced for the sake of closer cooperation between the Member States in the area of pharmacovigilance and in order to increase work-sharing.
The Community procedure for the assessment of serious safety issues for nationally authorised products is stream-lined through clear and binding initiation criteria for the Member States, rules to ensure that all products concerned are considered, an assessment procedure by the Pharmacovigilance Risk Assessment Advisory Committee, and rules for the subsequent follow-up as regards the terms of the marketing authorisations with a view to the adoption of harmonised measures across the Community.
Strengthened medicines safety transparency and communication should increase the understanding and trust of patients and health professionals in the safety of medicines and the regulatory system. Clear, EU coordinated messages about specific safety risk issues will improve the safe use of medicines.
Strengthening of the Eudravigilance database which should become the single point of receipt of pharmacovigilance information for medicinal products for human use authorised in the Community, therefore allowing all competent authorities to receive, access and share the information at the same time, with appropriate access to the Eudravigilance database data ensured.
Community coordination of communication about safety issues and establishment of a European medicines safety web-portal : The principles of communications about major new or changing safety issues should be laid down in the legislation. For issues affecting active substances authorised in more than one Member State, the Agency should coordinate the communications of the Member States. Furthermore, the Agency should set-up and maintain an European medicines safety web-portal as the main platform for announcements related to medicines safety dealt with at the EU level, and would include links to web-portals of the Member State competent authorities.
Introduction of a new ‘key information' section in the summary of the product characteristics and the package leaflet which accompany every medicinal product placed on the Community market.
Currently legislation requires a ‘detailed description of the pharmacovigilance system’ to be submitted in marketing authorisation applications and kept up to date for each individual marketing authorisation. The proposals simplify the existing requirement.
" Pharmacovigilance system master file ": In the marketing authorisation application only key elements of the pharmacovigilance system should be submitted, but this is balanced with a requirement for companies to maintain a detailed file on site.
Rationalising of risk management planning should ensure that safety evaluation of products is prospective (i.e. based on risk management planning) and that high-quality, non-promotional safety studies are done when justified by safety concerns.
In the provisions currently in force, applicants for a marketing authorisation may provide a risk management system for specific medicinal products if considered appropriate, and there is no explicit legal basis for competent authorities to request it. The proposals require a risk management system for each medicinal product to be newly authorised in the Community (or for existing products on the basis of safety concerns), which should be proportionate to the identified risks, potential risks, and the need for additional information on the medicinal product.
Harmonised guiding principles and a procedure for the supervision of non-interventional post-authorisation safety studies (i.e. safety studies of authorised products that are not clinical trials), in particular to ensure that they are non promotional, and the follow-up of any safety data generated in such studies.
Current reporting rules apply equally to all medicinal products, irrespective of their known risks, are submitted to several authorities where a product is authorised in more than one Member State, and lead to duplicative assessments as there is no provision to group assessments by products or substances. Besides, the notion of adverse reaction is linked to the side effects under normal conditions of use of medicinal products, and other side effects (resulting e.g. from medication errors or overdose) are not necessarily reported. The proposals are intended to make reporting proportionate to risks, to empower patients to report their side effects, and to ensure that overdoses and medication errors are reported.
Simplification of adverse reaction reporting. It is proposed to considerably simplify reporting rules by providing that all adverse reaction data are reported by marketing authorisation holders and Member States directly to the Eudravigilance database. As a result of this new reporting scheme, it will not be longer necessary to provide for different reporting rules for medicinal products authorised in accordance with the centralised procedure and medicinal products authorised in the Member States.
Monitoring of scientific literature by the Agency : The Agency is to take on a new task for the monitoring of selected scientific literature and for entering case reports of adverse effects onto the Eudravigilance database.
Medication errors that result in an adverse reaction should be reported to the competent authorities for medicines: The definition of adverse drug reaction should be clarified to make clear that companies report medication errors that result in an adverse reaction to the competent authorities for medicines and ensure that all the relevant Member State authorities share data (including between the authorities for medicines and any authorities for patient safety).
Make clear the legal basis for patients to report suspected adverse drug reactions.
Currently, periodic safety update reports are line listings of adverse reactions and, as for adverse reactions reports, are submitted for all medicinal products. Since there is no provision to group submissions and assessments by products or substances, this leads to duplicative submissions and assessments. The update of product information as a result of these assessments is not governed in detail by the actual legislation. The proposals simplify periodic safety update report submission by industry and make it proportional to the knowledge about the safety/risk of the product, would introduce work-sharing mechanisms for the assessments, with a prominent role in all cases by the Pharmacovigilance Risk Assessment Advisory Committee, and faster updating of product information through the establishment of clear procedures.
As a result of the submission of all adverse reaction data directly to the Eudravigilance database, the scope of periodic safety update reports is amended to become an analysis of the risk-benefit balance of a medicinal product rather than a detailed presentation of individual case reports. Besides, the requirements for periodic safety update reports are made proportional to the risks posed by medicinal products, and routine reporting is no longer necessary for products considered low risk or where reporting would be duplicative (with the possibility for ad-hoc requests for such products).
Explicit provision is made for the regulatory follow-up of assessments of periodic safety update reports , to ensure a clear link between pharmacovigilance evaluations and the review and updating of marketing authorisations authorised in the Community.
The proposals create the framework for the shared use of resources between competent authorities for the assessment and follow-up of periodic safety update reports, with a strong involvement of the Agency's Pharmacovigilance Risk Assessment Advisory Committee. A single assessment of periodic safety update reports for medicinal products authorised in more than one Member State, including for all products containing the same active substance, is foreseen. To further increase the efficiency of the system, a single assessment would also be conducted in the case of pharmacovigilance issues which concern products authorised by the Member States and products authorised by the Commission.
The proposal is based on Article 95 of the EC Treaty. Article 95, which prescribes the codecision procedure described in Article 251, is the legal basis for achieving the aims set out in Article 14 of the Treaty, which includes the free movement of goods (Article 14(2)), in this case medicinal products for human use.
While taking account of the fact that any regulation on medicinal products must be fundamentally aimed at safeguarding public health, since the Amsterdam Treaty came into force, Article 95 is the legal basis of the Community legislation for medicinal products for human use, including Directive 2001/83/EC and Regulation (EC) No 726/2004 i, since the differences between the national legislative, regulatory and administrative provisions on medicinal products tend to hinder intra-Community trade and therefore directly affect the operation of the internal market. Action to promote the development and authorisation of medicinal products is hence justified at a European level, with a view to preventing or eliminating these obstacles.
Community rules in the area of pharmacovigilance allow the best protection of public health according to the same standards across the Community. Divergent action by the Member States would prevent the full sharing of safety data and would increase the administrative burden on competent authorities and industry. A lack of coordination would deny the Member States access to the best scientific and medicinal expertise for the evaluation of the safety of medicines and for risk minimisation.
The impact analysis has shown that the ongoing efforts to improve the Community pharmacovigilance system through better implementation of the current legal framework, while bringing genuine improvements to the system, would be insufficient to make the step change improvement needed to reduce the major public health burden of adverse reactions to medicinal products.
The proposal has been carefully designed in close dialogue with stakeholders particularly those stakeholders upon which direct obligations are placed by the legal provisions, in order to better protect public health without imposing an unnecessary regulatory burden. The proposal builds on existing structures (including the European Medicines Agency and Member State competent authorities), procedures (including the existing reporting and referral procedures), resources (including the existing Community pharmacovigilance database) and practices (including work-sharing by the Member States). The proposal strives to maximise the efficiency of the processes and maximise the quality of the data collected and the quality of decisions taken thereby maximally benefiting public health. By increasing the efficiency of the Community pharmacovigilance system, the proposal will free up resource currently expended on meeting duplicative and complex administrative requirements and these resources can then be channelled into activities that directly promote and protect public health including better communications about the benefits and risks of medicines
The proposal does not go beyond what is necessary to achieve the objective pursued, i.e. to strengthen and rationalise Community pharmacovigilance system. The Impact Assessment has shown cost savings for the industry with an increase in costs for the regulators (national competent authorities and the Agency) that will be covered by industry fees. This increase in costs is modest compared to the projected savings to society including from reductions in hospitalisations and prolonged hospital stays caused by adverse reactions to medicinal products.
The proposal aims at modifying the existing provisions on pharmacovigilance for medicinal products for human use contained in Regulation (EC) No 726/2004 and in Directive 2001/83/EC, and an amending regulation and an amending directive are therefore considered the most appropriate legal instruments.
The proposal has no implication for the Community budget.
This initiative is referenced in the Commission Agenda Planning as 2008/ENTR/003. It is part of the Commission Legislative and Work Programme for 2008, under Annex 1 (Strategic and Priority initiatives) i.
The proposals contain key elements for the simplification of the Community system of pharmacovigilance, including: closer collaboration between the authorities which will maximise the expertise available; work-sharing and a strengthened role for the coordination group of the Member States to increase the efficient use of scarce resources and reduce duplication of effort; simplified adverse reaction and periodic safety update reporting; and the Pharmacovigilance System Master File of marketing authorisation holder.
The proposed act is of relevance to the EEA.