Explanatory Memorandum to COM(2001)404-2 - Amendment of Directive 2001/83/EC on the EC code relating to medicinal products for human use - Main contents
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| dossier | COM(2001)404-2 - Amendment of Directive 2001/83/EC on the EC code relating to medicinal products for human use. |
|---|---|
| source | COM(2001)404  |
| date | 26-11-2001 |
The purpose of the Community provisions concerning the placing on the market of medicinal products for human use is to guarantee a high level of public health protection and to enable the rules of the internal market to operate effectively. No medicinal product may be placed on the market unless its quality, safety and efficacy have been previously demonstrated. These guarantees must be maintained when it is actually placed on the market.
Contents
- II. Justification
- B. Legal basis and procedure
- III. Detailed content of the proposal
- A. Adaptation of definitions, terminology and certain concepts
- B. Generic medicinal products
- C. The decentralised procedure and the mutual recognition procedure (Chapter 4)
- D. Referral procedures
- E. Inspection and surveillance
- F. Pharmacovigilance
- G. Homeopathy (Chapter 2)
- H. Packaging
- I. Information
- IV. Administrative and legislative simplification
A. Aims
1. On 1 January 1995, new authorisation and monitoring procedures for medicinal products came into force i which replaced various procedures based on voluntary cooperation between the competent national authorities. The centralised procedure enables applicants to obtain from the Commission authorisation to place medicinal products on the Community market after evaluation by the European Agency for the Evaluation of Medicinal Products. This procedure is compulsory for biotechnological medicinal products and optional for innovative medicinal products. Where applicants wish to obtain authorisation to place other medicinal products on the market in more than one Member State, the mutual recognition procedure has been compulsory since 1998. This procedure is based on the evaluation carried out by the Member State (the 'reference Member State') which granted marketing authorisation, which is normally recognised by the Member States concerned by the same application for authorisation ("concerned Member States"). The European Agency for the Evaluation of Medicinal Products and the competent authorities in the Member States pursue a number of objectives, in particular the pooling of the Member States' potential in terms of scientific expertise in order to guarantee a high degree of public health protection, the free movement of pharmaceutical products, and more rapid access for the people of Europe to medicinal products and in particular to new generations of medicinal products. Now, six years later, these objectives are still valid. However, as a result of international and European developments, scientific progress and the forthcoming advent of new therapies, the existing legislation needs to be adapted and consideration must be given to the main features of future marketing authorisation procedures.
Regulation (EEC) No 2309/93 provided for the possibility of changing these procedures, since its Article 71 states that 'within six years of the entry into force of this Regulation, the Commission shall publish a general report on the experience acquired as a result of the operation of the procedures laid down in this Regulation, in Chapter III of Directive 75/319/EEC (medicinal products for human use( and in Chapter IV of Directive 81/851/EEC (veterinary medicinal products('.
On the basis of the provisions of this Article 71, an audit of the procedures and the operation of the Agency was commissioned from Cameron McKenna and Andersen Consulting. The results of this work are being analysed and developed in the 'Commission Report on the operation of Community marketing authorisation procedures for medicinal products' (COM....).
2. In the light of the experience acquired between 1995 and 2000 and of the analysis of the comments by the various parties concerned (the competent authorities in the Member States, pharmaceutical companies, associations of the pharmaceutical industry, professional associations of doctors and pharmacists, and associations of patients and consumers), the Commission felt it necessary to adapt certain provisions of Regulation (EEC) No 2309/93. It also appears necessary to adapt in an appropriate manner the general provisions relating to the placing on the market of medicinal products for human use, which have been consolidated in Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use, which is the subject of this proposal for amendment. The word 'adaptation' must be particularly stressed in this connection since, although procedural arrangements or other provisions need to be amended or added, neither the general principles nor the basic architecture of the system, as laid down by the original 1993 Regulation establishing the Agency, are disputed. The Commission is aware that, in view of the growth of the battery of therapeutic products available, and of the growing necessity for information and transparency with respect to medicinal products and their use, a number of Member States have developed a system for evaluating the relative efficacy of medicinal products, intended to allow a new medicinal product to be positioned with respect to those already on the market. Accordingly, in its Conclusions of 29 June 2000 on Medicinal Products and Public Health i, the Council has underlined the importance of the identification of medicines with significant added therapeutic value. The Commission is of the opinion that this type of assessment should not be undertaken within the marketing authorisation framework, where it is essential to maintain the fundamental criteria of quality, safety and efficacy. Even though it appears that action at a Community level may be useful, the Commission has not, therefore at this stage, made any proposals in this regard. After having conducted large consultations on this issue, the Commission will reflect on the possibility of making a proposal in the appropriate legal context.
3. The necessary adaptation must take account of the experience acquired in the six years during which the procedures have been implemented and of the rapid scientific developments in the pharmaceutical field. These considerations must also be seen in the light of ever-increasing globalisation, in particular between the world's three major pharmaceutical 'regions' of Europe, North America and Japan. Scientific globalisation is being accompanied by the globalisation of certain regulatory practices and in particular of the scientific and technical criteria for evaluating medicinal products. The increasingly rapid introduction of new technologies in the field of research and development relating to medicinal products requires an adaptable regulatory environment based on stable, well defined principles which are nevertheless truly international in scope. This 'global' dimension of regulatory requirements is surely one of the main new factors to be considered in comparison with the early 1990s, when the present Community marketing authorisation system was devised. Any regulatory environment applying to the authorisation of medicinal products can no longer be regarded as modern, effective and lasting if it develops in isolation. The Commission and the Member States are already very actively involved, through their participation in ICH i and VICH i, in the international discussions on technical and scientific requirements in the field of human and veterinary medicinal products. However, it is also very important that the regulatory framework of the Community marketing authorisation system should take due account of this new global environment so that the European Community can play a full part on the international stage alongside its - particularly American and Japanese - partners.
4. There is another new dimension in relation to the 1993 context which now has to be considered: the enlargement of the European Union. As in other areas, the future enlargement obviously raises the question of whether certain procedural arrangements for the regulation of medicinal products are appropriate and particularly whether it will be possible, in a context designed for 15 countries, for 20, 25 or 28 Member States to conduct scientific debates and take decisions effectively.
5. As part of all these regulatory and technical considerations, it will obviously be necessary to bear in mind the primary purpose of developing and subsequently marketing medicinal products: to achieve health benefits for patients. While the centralised authorisation system has proved to be effective for evaluating medicinal products, the effectiveness of the mutual recognition system should be improved, since it concerns to some extent new medicinal products but also medicinal products on which the files go back further or generic medicinal products. Particular account should be taken of generic medicinal products since, in the overall context of health systems, it should be made easier to place them on the market.
6. Any changes in the rules must maintain safety of use for the patient, market surveillance and pharmacovigilance. The analysis of the risk/benefit balance must remain the basis for any administrative decision on a medicinal product, irrespective of the authorisation procedures applied. Although the provisions in force have helped to ensure a high level of safety, it is necessary to improve certain existing arrangements with a view to speeding up action in emergencies and to increasing the effectiveness of the system of pharmacovigilance and market surveillance in order, inter alia, to take account of the fact that the market subject to such surveillance will increase in size as a result of the forthcoming enlargement of the European Union.
7. Lastly, the regulations must be adapted in order to take account of the experience acquired during these years of intensive cooperation between the Member States, the European Agency for the Evaluation of Medicinal Products and the Commission.
8. In general terms, the pharmaceutical legislation must be revised in the light of the objectives set out in the conclusions of the Commission Report:
- to provide a high level of health protection for the people of Europe and tighter surveillance of the market;
- to complete the internal market in pharmaceutical products taking account of the implications of globalisation and to establish a regulatory and legislative framework that favours the competitiveness of the European pharmaceuticals industry sector;
- to meet the challenges of the future enlargement of the European Union;
- to rationalise and simplify the system as far as possible, thus improving its overall consistency and visibility, and the transparency of procedures and decision-making.
The legal basis of this proposal is Article 95 of the Treaty. This Article, which provides for recourse to the co-decision procedure under Article 251, is the legal basis for achieving the objectives set out in Article 14 of the Treaty, which include the free movement of goods and hence of medicinal products for human use. The prime objective of all rules on the production and distribution of medicinal products must be to safeguard public health, but it must be achieved by means which do not restrict the free movement of medicinal products within the Community. Following the entry into force of the Treaty of Amsterdam, all the legislative provisions adopted by the European Parliament and the Council - except directives adopted on the basis of the executive powers conferred on the Commission and seeking to align the provisions on medicinal products - are adopted on the basis of this Article. This is because the differences between national laws, regulations and administrative provisions on medicinal products result in obstacles to intra-Community trade which directly affect the operation of the internal market. Legislative action by the Community is therefore justified in order to prevent or remove such obstacles.
(For greater ease of consultation, the Articles quoted as references are those of Directive 2001/83/EC as amended by this proposal).
1. The definition of medicinal product is adapted to take account of new therapies and their particular method of administration (Articles 1 and 2) (cellular therapy in particular).
2. In order to bring the text into line with current practice, it is proposed that both in the summary of the product characteristics (Article 11) and on the packaging (Articles 54 and 59), the name of the medicinal product be followed by the strength and the pharmaceutical form in order to improve the information for patients and practitioners.
3. The criteria for refusing, suspending and withdrawing marketing authorisations have been adapted and harmonised so that the key evaluation criteria of quality, safety and efficacy go hand in hand with the concept of risk/benefit balance, which is the basis of the authorisation and its continued validity (Articles 26, 116 and 117).
4. Since the possible duality of certain 'borderline' products (medical devices, cosmetics, biocides etc.) has led to differences of interpretation as to the applicable legislation, it is proposed that, when a product fully meets the definition of a medicinal product, but may also meet the definition of other regulated products, the pharmaceutical legislation should apply (Article 2(2)).
5. Adaptations are proposed to certain provisions relating to the marketing authorisation application file. These adaptations do not involve any substantive changes to the present provisions but are intended to bring certain legal provisions, the wording of which is sometimes outdated, more into line with current administrative, scientific and technical practices. Furthermore, they take account of the guidelines finalised by the ICH.
6. In order to ensure, as in the case of the centralised procedure, that the procedures are transparent, it is proposed that assessment reports and authorisations accompanied by summaries of the characteristics of the medicinal products authorised under the decentralised or mutual recognition procedure be made available to any interested party (Article 21).
1. In the case of abridged marketing authorisation procedures, it is proposed that the concept of 'essentially similar' medicinal product be abandoned since it actually refers to generic medicinal products. A definition of generic medicinal product is inserted into the text, together with a definition of reference medicinal product in relation to which the generic medicinal product is defined, in order to bring the text into line with the commonly accepted terminology (Article 10(2)).
2. Again to bring the text into line with practice, it is proposed that, for the reference medicinal product, the concept of actual placing on the market be abandoned and that only the requirement for it to have a marketing authorisation be retained (Article 10(1)). This is necessary in order to make it easier for generic medicinal products to gain access to the market.
3. The administrative protection period for data on the reference medicinal product must be harmonised at ten years (Article 10(1)). This period has been chosen in order to stipulate the same period irrespective of the type of marketing authorisation procedure and is the same as the period adopted under the centralised procedure. However, in order to promote research on new therapeutic indications with a significant clinical benefit and bringing an improvement to the quality of life and welfare of the patient, it is proposed that the applicant be granted an extra year of data protection in the case of therapeutic indications which meet the abovementioned conditions and are granted during this ten-year period. It is however necessary to maintain an appropriate balance between such innovations and the need to favour the production of generic medicines. It is therefore foreseen that this extra year will only be granted in the cases where the new indication is authorised during the first eight years of the ten years data protection period, with the aim of not hindering the emergence of a generic market (Article 10(1)).
4. Applicants for a marketing authorisation for a generic medicinal product may carry out the tests necessary for submitting the file before the end of the exclusivity period without this being regarded as an infringement of the rules on the protection of industrial and commercial property (Article 10(4)). The purpose of this provision is to prevent a large proportion of the requisite tests being conducted outside the Community, as is currently the case, but without affecting the date on which the generic medicinal products arrive on the market.
5. Lastly, in order to facilitate the harmonisation of existing reference medicinal products, it is proposed that an annual plan for gradual harmonisation be introduced (Article 30(2)). This will simplify the procedures for applying for a marketing authorisation for generic versions of these reference medicinal products under the mutual recognition or decentralised procedure.
1. The scope of these procedures is linked to that of the centralised procedure. In the proposal to amend Regulation (EEC) No 2309/93, it is proposed that the scope provided for in the original Regulation be maintained on the whole, except for certain amendments rendered necessary by the experience acquired during the past six years and by scientific and technological developments. Since the main amendment proposed is to make the centralised procedure compulsory for all new active substances appearing on the Community market, this means a significant change in the scope of the decentralised or mutual recognition procedure. Any medicinal product not compulsorily subject to the centralised procedure will be covered by the decentralised or mutual recognition procedure, on condition that it is intended for the markets of more than one Member State i.
These procedures are thus still optional for other medicinal products which represent a therapeutic innovation and will be the procedure of choice for generic medicinal products. It should be stressed in this connection that the procedures will also be open to generic medicinal products whose reference medicinal product has been authorised under the centralised procedure, since it is proposed that the Member States be given the option of authorising at national level the generic versions of medicinal products authorised by the Community on condition that they maintain the harmonisation achieved at Community level. In particular, the summary of the characteristics of the generic product must comply with that of the medicinal product authorised by the Community.
2. The mutual recognition procedure has been criticised because of difficulties encountered in practice. Under the present system, the Member States must recognise an initial authorisation granted by the reference Member State. It is always more difficult to go back on a scientific decision than to take an initial decision jointly as part of a scientific cooperation procedure. It is also proposed (a) to maintain the general principles of the mutual recognition procedure as laid down in the present rules on medicinal products which have already been granted a marketing authorisation in one of the Member States but whose holder wishes to make the product available to other Member States (Article 28 i and (2)), and (b) to add to it a new decentralised procedure for medicinal products not yet authorised in the Community (Article 28 i and (3)). There would be cooperation between Member States before the decision is taken on the basis of the evaluation conducted by one of them. This procedure is modelled on an existing procedure which has proved its worth, namely the procedure applied to the authorisation of major amendments to an existing authorisation.
3. The introduction of the mutual recognition procedure was facilitated by an informal working group, the 'Mutual Recognition Facilitation Group' (MRFG), in which representatives of the Member States meet. Since this group has proved to be effective and the amendment proposed to the procedure involves considerable cooperation between Member States, it is proposed that the group be given formal status and be called a co-ordination group (Article 27). Under the new mutual recognition or decentralised procedures, disagreements would be referred to this committee (Article 29 i and (2)) and, if it fails to arrive at a consensus, the matter would be referred to the European Agency for the Evaluation of Medicinal Products (Article 29(3)).
4. It is proposed in the case of both Regulation (EEC) No 2309/93 and the mutual recognition or decentralised procedure that the obligation to renew the marketing authorisation every five years be removed (Article 24(1)). However, to take account of this removal of the obligation to renew the authorisation every five years, the present proposal stipulates that any marketing authorisation which is not followed within two consecutive years by the actual placing on the market of the medicinal product concerned shall cease to be valid (Article 24 i and (3)). The removal of the obligation of renewal goes hand in hand with a strengthening of the pharmacovigilance and market-surveillance procedures.
The referral procedures come into play if a Member State cannot agree with the assessment report and the summary of product characteristics drawn up by another Member State (Article 29), if there is a lack of harmonisation in the decisions taken by the Member States (Article 30), or if the interests of the Community are involved (Article 31). Although few procedures are referred in this way, such referrals have given rise to very many discussions, particularly regarding interpretation and practical application. In particular in cases where a Member State cannot agree with the evaluation or authorisation by another Member State, it is proposed that referral be made automatic, since experience has shown that, in order to avoid referral, firms systematically withdraw their applications in Member States which are not in favour of granting authorisation. However, it is proposed that in such cases the Member States which are in favour of granting authorisation be allowed to do so on the understanding that, depending on the result of the referral, they may subsequently have to amend it. With regard to referrals on matters of Community interest, and in the light of the experience acquired, it is necessary to provide for an appropriate procedure, particularly in the case of referrals concerning an entire therapeutic class or all medicinal products containing the same active substance (Article 31). In both these cases, the number of medicinal products concerned may be very large, and the aim is to ensure that the procedure is effective.
Lastly, in order to make this procedure more effective in terms of deadlines, it is proposed that its overall length be reduced from 90 days to 60 days (Article 32(1)).
Following referral procedures, the Commission must take a decision, which must be applied by the Member States (Articles 33 and 34). The Commission decision-making process has been the subject of much criticism, in particular on account of its length. As in the case of the decisions which the Commission must take following applications for marketing authorisation under the centralised procedure, this process needs to be reorganised. At present the decision-making procedure is subject to a type III (b) 'comitology' procedure i. It should be noted first of all that from the outset the Commission has always followed the Agency's opinion on highly scientific matters. Furthermore, the opinions have generally been obtained by written procedure without a formal meeting of the regulatory committee, since this possibility is provided for by the legislation. The rare cases requiring a formal vote during a meeting arose during the system's 'running-in' period.
In view of the experience acquired and of the adoption of a new 'comitology' Decision by the Council on 28 June 1999 (1999/468/EC) i, this decision-making procedure now needs to be re-assessed. It is also proposed that decision-making be subject to a consultation procedure under Decision 1999/468/EEC if the draft submitted by the Commission follows the Agency's scientific opinion or, in all other cases, to a management procedure under this Decision. In both cases, the deadlines are adapted in order to shorten the phase in which the Member States are consulted (Article 34(2)).
1. The overall quality of medicinal products is based both on the evaluation of the information submitted as part of the application for marketing authorisation and on the constant monitoring of the quality of the manufactured and marketed medicinal products to establish whether they comply with the data supplied. The monitoring of the quality of the manufacture and control of medicinal products must broadly take account of consumer protection, the completion of the internal market and the international dimension, in particular the agreements with non-member countries on mutual recognition. Quality guarantees are based mainly on a quality-assurance system which includes compliance with good manufacturing practice and on inspections by the competent authorities to ensure that all the legal requirements are complied with. The present Regulation covers medicinal products but is not specifically intended to apply to starting materials. It is therefore proposed that it be extended to cover active substances used as starting materials in the manufacture of medicinal products (Article 111(1)). Since the Member States adopt differing approaches, the harmonisation of the application of good manufacturing practice for these substances should be proposed. Detailed guidelines setting out appropriate practical provisions will be adopted. The same applies to the system for inspecting the manufacture of these active substances. Lastly, it is proposed that provision be made for issuing certificates of good manufacturing practice attesting compliance with the relevant requirements.
2. It is also necessary to reinforce the general provisions on inspection of medicinal products, if necessary in conjunction with the European Pharmacopoeia (Article 111 i and (5)), and to increase Community coordination by introducing a Community information register on good manufacturing practice (Article 111 i and (7)) and setting up a Community system of data on manufacturing authorisations (Article 40(4 )). It is proposed that the inspection system based on the recognition of inspections carried out by one of the Member States be supplemented by a procedure for settling disagreements between Member States on the results of an inspection (Article 122). It is also proposed that the possibility of inspecting pharmacovigilance sites and conducting inspections in non-member countries be added (Article 111(4)).
On the basis of the experience acquired, it is necessary to place greater emphasis on the need for a preventive approach with regard to pharmacovigilance. There has been considerable technical progress at both Community and international level. Exchanges of data between the Member States, marketing authorisation holders and the European Agency for the Evaluation of Medicinal Products are increasingly dependent on information technologies. There should be a rapid exchange of the data collected by all the partners. Following the agreement on the MedDRA, the use of this medical terminology, drawn up by ICH and officially launched in 1999, should be made compulsory in the interests of public health and to ensure that notifications of adverse reactions to medicinal products are consistent in a multilingual environment (Article 106). It is also important to ensure that the Member States' pharmacovigilance systems are harmonised and consistent so that all medicinal products authorised in the Community can be effectively monitored. In connection with the proposal to abolish the five-yearly renewal requirement, and to increase the efficacy of the system, it is proposed that the deadlines for the compulsory submission of periodic safety update reports be shortened (Article 104). It is also proposed that the Commission should, where urgent action is necessary, be able to request the Member States to adopt temporary measures with immediate effect (Article 107). Furthermore, it is proposed that the inspections regarding the obligations on marketing authorisation holders be reinforced (Article 111). Lastly, it is proposed that the coordination between Member States for the pharmacovigilance of medicinal products subject to the mutual recognition or decentralised procedure be improved (Article 104(5)).
In order to create an additional stage in the harmonisation of this category of medicinal products, the proposal provides for the introduction of a limited mutual recognition procedure. Furthermore, in order to make it easier to place them on the market, invented names may be used, and it is proposed that the blanket prohibition of public advertising be removed (Article 100).
The rules stipulate that the packaging of medicinal products must contain a package leaflet for patients. The order of the headings which must figure in this package leaflet is compulsory. On the basis of the experience acquired, it is necessary to adapt the rules and to propose an order of headings corresponding to patients' needs and habits (Article 59).
In view of the spread of new information technologies and of growing consumer demand for information, it is proposed that, on an experimental basis, the possibilities of disseminating information on prescription-only medicinal products be extended. Public advertising is not currently authorised for prescription-only medicinal products. This provision has been interpreted as forbidding also all kind of information to the public, and only advertising and information addressed to health professionals being possible. It is proposed that there should be public advertising of three classes of medicinal products. This type of information would be subject to the principles of good practice to be adopted by the Commission and to the drafting of a code of conduct by the industry. After five years of operation, an evaluation would be carried out in order to determine what action should be taken (Article 88(2)) in the wake of this trial.
The present proposal takes due account of the vast amount of work to consolidate the directives in the field of Community legislation on medicinal products for human use (31 consolidated texts). It also introduces provisions to rationalise and speed up the procedures relating to marketing authorisations for medicinal products for human use
V. Consultations prior to the drafting of the proposal
The Commission has had an audit carried out by an external consultant, as stated in the explanatory memorandum. There have been several consultations, meetings and hearings with all the parties concerned. The Commission has also received numerous reports and discussion papers from these parties, particularly the Member States, patients' associations, European federations of the pharmaceutical industry, pharmacists and distributors. All these documents and their analysis have been taken up in the Commission report to the European Parliament and the Council on the operation of the abovementioned marketing authorisation procedures in the Community (COM ....).