VOLUME 2A Procedures for marketing authorisation CHAPTER 3 COMMUNITY REFERRAL November 2002

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1 EUROPEAN COMMISSION ENTERPRISE DIRECTORATE-GENERAL Single market : management & legislation for consumer goods Pharmaceuticals : regulatory framework and market authorisations Brussels, ENTR/F2/BL D(2001) Final Revision 1 NOTICE TO APPLICANTS VOLUME 2A Procedures for marketing authorisation CHAPTER 3 COMMUNITY REFERRAL November 2002 This Chapter 3 Community Referral will be included in The Rules governing Medicinal Products in the European Community The Notice to Applicants Volume 2A Procedures for marketing authorisation Rue de la Loi 200, B-1049 Bruxelles/Wetstraat 200, B-1049 Brussel - Belgium - Office: AN88 1/3. Telephone: direct line (+32-2) , switchboard Fax: Telex: COMEU B Telegraphic address: COMEUR Brussels.

2 CHAPTER 3 COMMUNITY REFERRAL Community referral 2 Final Revision 1 November 2002 Introduction Community pharmaceutical legislation has created a binding Community arbitration mechanism which may be invoked on the basis of the following articles: 1. Article 29 of Directive 2001/83/EC ( Mutual Recognition referral ) 2. Article 30 of Directive 2001/83/EC ( Divergent decision referral ) 3. Article 31 of Directive 2001/83/EC ( Community interest referral ) 4. Articles 35, 36 and 37 of Directive 2001/83/EC ( Follow-up referrals ) Whenever this arbitration mechanism is being invoked, a scientific evaluation of the matter is undertaken by the EMEA s Scientific Committee, the Committee for Proprietary Medicinal Products (CPMP), leading to an opinion from which the Commission draft a single decision binding the Member States and applicant(s)/marketing Authorisation Holder(s). The specific conditions under which a referral procedure may be started and the persons/institutions entitled to ask for referral differ in each of the cases mentioned above and are specified in detail in sections 1 to 4. Under certain, well-defined circumstances (urgency) Member States may take unilateral action whilst waiting for the outcome of a Community referral. These cases are illustrated in section 5. The procedural elements of the referral procedure are laid down in 32, 33 and 34 of Directive 2001/83/EC. These procedural elements are similar for all types of Community referral and are described in section 6. This common procedural part gives clear practical guidance on what needs to be done in the referral procedure. 1. Article 29 of Directive 2001/83/EC ( Mutual Recognition referral ) Who may start this referral? Member States who are concerned by a Mutual Recognition procedure. Which Member State(s) is (are) concerned? All Member States involved in the Mutual Recognition Procedure (Reference Member States and Concerned Member States) In which situation? In the course of a Mutual Recognition procedure. 1

3 Community referral For which reasons? Concern that authorisation of the medicinal product might present a risk to public health concerning the quality, safety or efficacy of the medicinal product. If, within the 90-days period of a Mutual Recognition procedure which has been triggered by an applicant (Article 28 of Directive 2001/83/EC) or which has been triggered by a Member State (Article 17 and 18 of Directive 2001/83/EC), a Member State considers that authorisation of the medicinal product concerned may present a risk to public health it shall follow the next steps foreseen in Article 29 of Directive 2001/83/EC: Information of other parties involved The Member State(s) which raise(s) the objections informs the applicant(s)/marketing Authorisation Holder(s), the Reference Member State, any Concerned Member State(s), and the CPMP. The Member State(s) state(s) its/their reasons in detail and indicate(s) what action may be necessary to correct any defect in the application. Preconflictual settlement and hearing of the applicant ( break-out session ) Following information about the problems perceived by a Member State, all the Member States concerned use their best endeavours to reach agreement on the action to be taken in respect of the application. They provide the applicant(s)/marketing Authorisation Holder(s) with the opportunity to make his/their point of view known orally ( MRFG break-out session ) or in writing, should the Member State require it. If agreement can be reached, the Mutual Recognition procedure will be continued in accordance with the results of the agreement achieved. Referral However, if the Member States have not reached agreement within 90 days after the start of the Mutual Recognition procedure, they refer the matter(s) to the CPMP for the application of the procedure laid down in Article 32. The question(s) referred to the CPMP must be based on public health concerns and should be precise. The Concerned Member State(s) making the referral draft them. A notification form for a referral to the CPMP/EMEA is added in the annex. Together with this referral, the Reference Member State provide the CPMP with a detailed statement of the matter(s) on which the Member States concerned have been unable to reach agreement and the reasons for their disagreement. The applicant is provided with a copy of this information. This detailed statement should focus on the following four essential elements: i. description of the product: the latest available SPC as achieved during the mutual recognition procedure; ii. description of the scientific discussion during the various stages of the Mutual Recognition procedure between the Reference Member State and Concerned Member State(s), including a brief summary of the resolution of other major issues between day 0 and day 60; iii. description of discrepancies, giving a clear statement of the issues at referral and a proposal for question(s) to be addressed by the applicant; iv. initial assessment report of the Reference Member State. 2

4 Community referral Duties of the applicant for mutual recognition following a referral As soon as the applicant(s)/marketing Authorisation Holder(s) is/are informed that the matter has been referred to the CPMP, the applicant(s)/marketing Authorisation Holder(s) forward to the EMEA a copy of the application he/they had submitted to the competent authorities of the Member States concerned, together with the information and particulars referred to in Articles 8, 10, 11 and 21 of Directive 2001/83/EC. Members of CPMP could receive a copy of the dossier on request only. The fee for referral is payable by the applicant(s)/marketing Authorisation Holder(s) to the EMEA at the initiation of the referral. What is the scope of the referral? The CPMP is called upon to issue an opinion on the concerns that authorisation of the medicinal product concerned might present a risk to public health. Legislation specifies that risk to public health refers to the quality, safety or efficacy of the medicinal product (Article 17 (2) of Directive 2001/83/EC). This definition is very wide and anything which might impact the quality, safety or efficacy may be a legitimate reason for starting a Mutual Recognition referral. If the CPMP is asked whether a medicinal product presents a risk to public health, it can therefore not limit its answer to those aspects specifically raised by a Member State but it must take into account every consideration and all information regarding the quality, safety or efficacy of the medicinal product which are related to that particular public health concern. The CPMP may consider all aspects, which are necessary to draft the SPC which will be annexed to the opinion of the CPMP and to the decision of the Commission as provided in Articles 32, 33 and 34 of Directive 2001/83/EC. The Decision of the Commission must be implemented in all Member States concerned. Can the application be withdrawn or the referral be stopped? Before the notification of a referral to the CPMP An application for Mutual Recognition of a marketing authorisation may be withdrawn by the applicant(s)/marketing Authorisation Holder(s) at any time in any Member State where the application has been submitted. By withdrawing an application, the applicant(s)/marketing Authorisation Holder(s) may avoid an Article 29 referral. However, if there remains an issue of Community interest to be resolved, Member State(s) or the Commission may start an Article 31 referral. After the notification of a referral to the CPMP The possibility of a preconflictual settlement and the hearing of the applicant give an opportunity to clarify misunderstandings between Member States and to sort out issues before a referral takes place. Once a referral has been endorsed by the CPMP it must therefore be assumed that the procedure concerns a risk to public health referring to the quality, safety or efficacy of a medicinal product already authorised in the EU. Once started, the procedure may only be stopped if the applicant(s)/marketing Authorisation Holder(s) withdraw the concerned product/the application in all EU Member States. In such case, the CPMP may decide to close the referral procedure or to continue it, if there still is a public health matter to be discussed. It is in the public interest and in the interest of the Community that questions on possible risks to public health are answered, and that all medicinal products authorised in the EU fulfil the requirements of quality, safety and efficacy. 3

5 Community referral Timeframe The CPMP considers the matter(s) and issues an opinion within 90 days of the date of the start of the procedure. In case of urgency, on a proposal from its Chairman, the CPMP may agree to impose a shorter deadline. Details on the timetable of the referral are described in section Article 30 of Directive 2001/83/EC ( Divergent decision referral ) Who may start this referral? Any Member State(s), the Commission or the applicant(s)/marketing Authorisation Holder(s) of a particular medicinal product. Which Member State(s) is (are) concerned? Member States concerned are those where the marketing authorisation of the medicinal product concerned has been granted, refused, suspended or withdrawn (as the case may be). In which situation? When divergent decisions have been taken by Member States related to this particular medicinal product. For which reasons? Divergent national decisions taken by Member States concerning the authorisation, or the suspension or withdrawal of a particular medicinal product. If Member States have adopted divergent decisions concerning the authorisation of a particular medicinal product or its suspension or withdrawal from the market, a Member State, or the Commission, or the Marketing Authorization Holder may refer the matter to the CPMP. Article 30 of Directive 2001/83/EC covers all marketing authorisations which have been issued by Member States, both purely national marketing authorisations and national marketing authorisations which have been issued following a mutual recognition procedure for this particular medicinal product. Article 30 may be invoked, for instance, in the following cases: where the same medicinal product has been nationally authorised in two or more Member States and the authorisations, particularly the indications, diverge significantly; where a medicinal product, with a national marketing authorisation in some or all the Member States, is suspended or withdrawn for quality, safety or efficacy reasons in some -but not all- Concerned Member States; where a medicinal product is nationally authorised in some or all Member States and one of the authorisations is subsequently varied, introducing a divergence versus the other national authorisations. 4

6 Community referral Procedural steps leading to an Article 30 referral In advance of making a referral under this article, it is recommended that informal discussions take place between the applicant(s)/marketing Authorisation Holder(s) and the Member State (s) concerned. The referrer (Member State, applicant(s)/marketing Authorisation Holder(s) or the Commission) clearly identifies the question that is referred to the CPMP for consideration, together with a detailed explanation of the issue(s) raised. A notification form for a referral to the CPMP/EMEA is added in the annex. The CPMP can only reach a satisfactory conclusion on the referral when the question asked is sufficiently precise and has a well-defined scope. If the referrer is a Member State or the Commission, the applicant(s)/marketing Authorisation Holder(s) must be informed on the issue(s) raised in the referral. Following notification and detailed explanation of the referral by a Member State, or the Commission, the applicant(s)/marketing Authorisation Holder(s) and the Member States concerned forward to the EMEA all available information. In particular, for the applicant(s)/marketing Authorisation Holder(s), copies of the dossiers of the national marketing authorisations/application in the Member States concerned, relating to the matter in question. The fee for referral is payable by the applicant/marketing Authorisation Holder to the EMEA at the initiation of the referral. What is the scope of the referral? The CPMP is called upon to issue an opinion on the area(s) of divergence amongst the national divergent decisions, framed on the question referred to it. Thus the scope of the referral is limited to the resolution of the divergences between the national decisions. The CPMP may, however, consider aspects other than those explicitly mentioned in the referral which are necessary to obtain a harmonised solution for this particular medicinal product under consideration, as an SPC is annexed to the opinion of the CPMP and the decision of the Commission as provided in Articles 32, 33 and 34 of Directive 2001/83/EC. The decision of the Commission must be implemented in all Member States concerned. Can the referral be refused or stopped? A referral can only be accepted as admissible by the CPMP if divergent decisions on the authorisation, or the suspension or withdrawal of a particular medicinal product have been taken by Member States. Once endorsed by the CPMP as admissible, the referral can only be stopped if Marketing Authorisation Holder(s) withdraw the concerned medicinal product from all EU markets. In such case the CPMP may decide to close the referral procedure or to continue if there still is public health matter to be discussed. It is in the public health interest and in the interest of the Community that uncertainties arising from divergent decisions concerning medicinal products in the EU are answered. Timeframe For referrals under Article 30, the CPMP considers the matter and issues a reasoned opinion within 90 days of the date of the start of the procedure. This period may be 5

7 Community referral extended by a further 90 days. In case of urgency, on a proposal from its Chairman, the CPMP may agree to impose a shorter deadline. Details on the timetable of the referral are described in section Article 31 of Directive 2001/83/EC ( Community interest referral ) Who may start this referral? Member States, the Commission, the applicant(s)/ Marketing Authorisation Holder(s) of the concerned medicinal product. In which situation? Whenever the interests of the Community are involved. This may occur when a decision has to be taken on a request for a marketing authorisation, or on the suspension, or withdrawal of a marketing authorisation or on any other variation to the terms of a marketing authorisation which appears necessary. For which reasons? This referral may be started in specific cases where the interests of the Community are involved. The expression interest of the Community has a very broad meaning. It refers particularly to the interests of the Community public health related to a medicinal product which is on the market in the European Union in the light of new data related to quality, safety and efficacy or new pharmacovigilance information but is not limited to this case. The interests of the Community are set out in the EC Treaty and cover amongst others the creation of an internal market, the attainment of a high level of health protection, strengthening of consumer protection, avoidance of distortion of competition and environmental protection. Whenever a Member State or the Commission or applicant(s)/marketing Authorisation Holder(s) invokes Article 31, there is an obligation to demonstrate the existence of a Community interest. According to Article 31 of Directive 2001/83/EC, the Member States or the Commission or applicant(s)/marketing Authorisation Holder(s) may, in specific cases where the interests of the Community are involved, refer the matter to the CPMP before reaching a decision on a request for a marketing authorisation, or on the suspension or withdrawal of an authorisation, or on any other variation to the terms of a marketing authorisation which appears necessary, in particular to take account of the information collected in accordance with Chapter IX of Directive 2001/83/EC. This provision covers all marketing authorisations (also centralised medicinal products/applications). Procedural steps leading to an Article 31 referral: The referrer (Member State(s), applicant(s)/marketing Authorisation Holder(s) or the Commission) clearly identifies the question, which is referred to the CPMP for consideration together with a detailed explanation of the issue(s) raised. A notification form for a referral to the CPMP/EMEA is added in the annex. 6

8 Community referral The CPMP can only reach a satisfactory conclusion to the referral when the question referred is sufficiently precise and has a well-defined scope. If the referrer is a Member State or the Commission, the applicant(s)/marketing Authorisation Holder(s) must be informed on the issues raised in the referral. Following the start of the referral procedure by a Member State or the Commission, the applicant(s)/marketing Authorisation Holder(s) forward to the EMEA all available information relating to the matter in question (as highlighted in the list of questions). The fee for referral is payable by the applicant(s)/marketing Authorisation Holder(s) within 30 days following the referral to the EMEA. What is the scope of the referral? The CPMP is called upon to issue an opinion on a matter involving Community interests, framed on a question referred to it. In principle the scope of the referral is limited to the resolution of issues raised in the question and involving Community interests. However, the CPMP may consider aspects other than those explicitly mentioned in the referral which are necessary to evaluate quality, safety, and efficacy of the medicinal product under consideration, and which are necessary to obtain a SPC that is annexed to the opinion of the CPMP and the decision of the Commission as provided in Articles 32, 33 and 34 of Directive 2001/83/EC. The decision of the Commission must be implemented in all Member States concerned. Can the referral be refused or stopped? A referral can only be accepted as admissible by the CPMP if an issue of Community interest is at stake. Once endorsed by the CPMP as admissible, the referral can only be stopped if applicant(s)/marketing Authorisation Holder(s) withdraw the concerned product from all EU markets. The CPMP may decide to close the referral procedure unless there still is a public health matter to be discussed. Timeframe For referrals under Article 31, the CPMP considers the matter and issues a reasoned opinion within 90 days of the date of referral. This period may be extended by a further 90 days. In case of urgency, on a proposal from its Chairman, the CPMP may agree to impose a shorter deadline. Details on the timetable of the referral are described in section Articles 35, 36 and 37 of Directive 2001/83/EC ( Follow-up referrals ) Who may start this referral? Member States or the Marketing Authorisation Holder. Which Member State(s) is(are) concerned? Member States where a marketing authorisation has already undergone a Community procedure. 7

9 Community referral In which situation? In all cases where a marketing authorisation has already undergone a Community procedure and a Member State considers that: By reference to Article 36 of Directive 2001/83/EC, a change/variation, suspension or withdrawal of a harmonised marketing authorisation is necessary for the protection of public health; By reference to Article 5(3) or 7(5) of Regulation (EC) 541/95, Mutual Recognition by one or more national competent authorities of the draft decision of the Reference Member State on a variation is not possible. For which reasons? In accordance with the general principle that achieved harmonisation must be maintained, Community pharmaceutical legislation has created an arbitration mechanism which aims to resolve divergences arising between Member States AFTER harmonisation has been achieved. For Type I Variations, Article 5(3) of Regulation (EC) 541/95 states that in case of divergent positions among the national competent authorities of the Concerned Member States leading to a refusal, the Marketing Authorisation Holder may refer the matter to the EMEA for application of Article 35 (2) of Directive 2001/83/EC which refers to the procedures laid down in Articles 32, 33 and 34 of Directive 2001/83/EC. For Type II Variations, Article 7(5) of Regulation (EC) 541/95 states that if the Mutual Recognition by one or more national competent authorities of the draft decision of the national competent authority of the Reference Member State is not possible, reference is made to the provisions of Article 35 (2) of Directive 2001/83/EC which refers to the procedures laid down in Articles 32, 33 and 34 of Directive 2001/83/EC For medicinal products authorised by Member States following an opinion of the CPMP given in accordance with Article 4 of Directive 87/22/EEC before 1 January 1995 (exconcertation medicinal products): Article 37 of Directive 2001/83/EC applies in like manner. The Articles 32, 33 and 34 of Directive 2001/83/EC apply by analogy to variations for medicinal products subjected to Commission s referral. Procedural steps leading to Articles 35, 36 and 37 referrals: By analogy to Article 31 referral, the procedural steps apply in a like manner. What is the scope of the referral? The CPMP is called upon to issue an opinion on the matter of variation of the terms of a marketing authorisation, its suspension or withdrawal, framed on a question referred to it. It is considered that variation, suspension or withdrawal is necessary for protection of public health. However, the CPMP may consider aspects others than those explicitly mentioned in the referral, which are necessary to obtain a harmonised solution for the medicinal product under consideration. In case of an opinion recommending the maintenance or variation of 8

10 Community referral (a) marketing authorisation(s), a SPC is annexed to the opinion of the CPMP and to the decision of the Commission as provided in Article 32, 33 and 34 of Directive 2001/83/EC. The decision of the Commission must be implemented in all Member States concerned. Can the referral be refused or stopped? A referral can only be accepted as admissible by the CPMP if variation of marketing authorisation, its suspension or withdrawal is necessary for protection of public health and if Mutual Recognition by one or more national competent authority has not been achieved. Once endorsed by the CPMP as admissible, the referral can only be stopped if applicant(s)/marketing Authorisation Holder(s) withdraw the concerned product from all EU markets. In such case the CPMP may decide to close the referral procedure or to continue if there is still public health matter to be discussed. Timeframe For referrals under Articles 36 and 37, the CPMP considers the matter and issues a reasoned opinion within 90 days of the start of the referral. By analogy to Article 31 referral, this period may be extended by a further 90 days. In case of urgency, on a proposal from its Chairman, the CPMP may agree to impose a shorter deadline. Details on the timetable of the referral are described in section Unilateral Action by Member States in urgent cases As soon as concern about a medicinal product has a European dimension where the issue concerns products which are authorised in more than one Member State and/or is of Community interest, divergence between Member States and the resulting need to change, or suspend or withdraw marketing authorisation must be sorted out and determined at European level within the Community arbitration mechanisms described above and unilateral national action is not acceptable. However, Community pharmaceutical legislation does recognise the need for unilateral urgency measures by Member States where urgent action is essential to protect public health and until a definitive action is adopted. In accordance with Article 36 (2) of Directive 2001/83/EC, in these specific cases, the Member States may temporarily take national measures suspending the marketing and use of a medicinal product. They must inform the Commission, the EMEA and the other Member States no later than the following working day. In addition it should be noted that Article 107 of Directive 2001/83/EC places an obligation on Member States to inform the EMEA and the Marketing Authorisation Holder of the need of any variation, suspension or withdrawal of a marketing authorisation for any medicinal product even purely nationally authorised products resulting from the evaluation of pharmacovigilance data. If Member States suspend the marketing of the concerned product, the EMEA has to be informed at the latest the following working day. The EMEA will include the issue on the agenda of the following CPMP meeting for information/discussion leading - if considered appropriate- to the start of a referral procedure, to be triggered by either a Member State or the Commission. 9

11 Community referral 6. Procedural elements Notwithstanding the legal provisions described below (Articles 32, 33 and 34 of Directive 2001/83/EC), it is suggested to carry out some preliminary procedural steps in order to streamline the operation of the Community referral procedure. In advance of making a referral, a notification should be sent to the EMEA, including: The intention to submit a referral; Clear and concise identification of the question to be referred to the CPMP, indicating the medicinal product concerned, presentations, pharmaceutical forms and/or strengths, applicant(s)/marketing Authorisation Holder(s); Proposal on documentation to be provided in support of the referral; Where appropriate request for a meeting with the EMEA to discuss legal, regulatory and procedural issues linked to the referral. When an issue is referred to the CPMP, each Member State should make available to the EMEA before the end of the first CPMP meeting following the referral a list of the names of the medicinal product(s) affected by the referral, applicant(s)/marketing Authorisation Holder(s), strength(s), pharmaceutical form(s), route(s) of administration, packaging and pack size(s) available in their territory, when applicable. The Member State or applicant(s)/marketing Authorisation Holder(s) should submit all available information relating to the matter in question to the CPMP. In cases where the referral follows the withdrawal or the suspension of the marketing of a medicinal product in a Member State, that Member State should immediately forward all information relating to this action to the CPMP members, the competent authorities of the Member States and the EMEA. In the case of referrals from (an) applicant(s)/marketing Authorisation Holder(s), the referral should be accompanied by expert reports which take into account the current regulations and which have been updated to include data supporting the reasons for referral. In addition the applicant(s)/marketing Authorisation Holder(s) should ensure that all available information relating to the matter in question is forwarded to the CPMP members, the competent authorities of the Member States, and the EMEA. To ensure a smooth implementation of the above-mentioned requirements, the EMEA will inform the applicant(s)/marketing Authorisation Holder(s) for each referral on the documentation needed as well as on the number of copies to be sent to the Rapporteur, the Co-Rapporteur and other CPMP members. Timeframe After notification of the referral the CPMP considers the matter concerned and issues a reasoned opinion within 90 days of the date of the referral. If the CPMP has to deal with an Article 30 or Article 31 referral (or by analogy also for Articles 36 and 37 referrals), it may extend this period to 180 days. In case of urgency, on a proposal from its Chairman, the CPMP may agree to impose a shorter deadline. 10

12 Community referral Organization of work within the CPMP In order to consider the matter, the CPMP appoints one of its members to act as rapporteur. The appointment of a Rapporteur and, if appropriate, of a Co-Rapporteur is made by the CPMP on a case-by-case basis. In cases where a number of referrals are made, related to a class effect, it is not necessary to appoint a (Co-)Rapporteur for each medicinal product, one (Co-)Rapporteur may be appointed for a class of products. Once the appointment of the (Co- )Rapporteur(s) has been made, the EMEA informs the applicant(s)/marketing Authorisation Holder(s) and communicate the name of the EMEA Product Team Leader in charge. The CPMP may also appoint individual experts to advise it on specific questions. When appointing experts, the Committee defines their tasks and specifies the time limit for the completion of these tasks. The EMEA informs the applicant(s)/marketing Authorisation Holder(s) on the documentation needed as well as on the number of copies to be sent to the Rapporteur, the Co-Rapporteur and other CPMP members. The EMEA also informs the applicant(s)/marketing Authorisation Holder(s) about the fees to be paid in accordance with Council Regulation (EC) No. 297/95. At the first CPMP meeting following the referral, the CPMP formulates the question(s) to be addressed to the applicant(s)/marketing Authorisation Holder(s) and discusses, on the basis of the proposal from the party making the referral, the scope of the documentation actually requested or needed. The CPMP may also take into account any other information at its disposal which concerns the quality, safety and efficacy of the medicinal product and which may help in arriving at its opinion. The CPMP informs the EMEA on whether members wish to receive full or parts of the documentation, indicating the number of copies required. Hearing of the applicant/marketing Authorisation Holder In the cases referred to in Articles 29 and 30 and in the case of Articles 35, 36 and 37 referrals, before issuing its opinion, the CPMP provides the applicant(s)/marketing Authorisation Holder(s) with an opportunity to present written or oral explanations. In the case referred to in Article 31 (Community interest), the applicant(s)/marketing Authorisation Holder(s) may be asked to explain himself/themselves orally or in writing. Even though the right for a hearing is not obligatory in all cases, the CPMP should, as a matter of good administrative practice, always grant applicant(s)/marketing Authorisation Holder(s) the right to present his/their views. Clockstop provisions The CPMP may suspend the time limit of 90/180 days in order to allow the applicant(s)/marketing Authorisation Holder(s) to prepare and submit explanations. Timetable for the referral Day 0 Notification of a referral to the CPMP Day 1 First meeting of the CPMP following the referral to discuss the question(s) referred to the CPMP and the appointment of the Rapporteur/(Co)-Rapporteur, where appropriate). Adoption by the CPMP of the question(s) to be addressed by the applicant(s)/marketing Authorisation Holder(s). 11

13 Community referral Clock stop For the applicant(s)/marketing Authorisation Holder(s) to answer the list of questions raised by the CPMP. Clock re-start First CPMP meeting after submission of responses (including (day 2) proposed English SPC, if applicable). Translation into English of the Reference Member State Assessment Report should also be submitted with the responses, if applicable. Adoption by the CPMP of timetable for the rest of the procedure Day 45 (Co-)Rapporteur(s) prepare(s) a report on the written comments from the applicant(s)/marketing Authorisation Holder(s) together, if applicable, with the draft SPC to be annexed to the opinion. Day 55 Comments from CPMP members on the (Co-)Rapporteur(s) assessment report(s) plus draft SPC (if applicable). Day 60 Discussion at the CPMP Need to have an oral explanation: (Co-)Rapporteur(s) and EMEA to liaise with the applicant(s)/marketing Authorisation Holder(s) Applicant(s)/Marketing Authorisation Holder(s) should submit the translations of draft SPC in all official languages* (if applicable). Clock stop If necessary, for the preparation and submission of oral explanations Clock re-start If necessary, oral explanations Day 90 * Adoption of the CPMP opinion with annexes, if applicable as provided in Article 32 of Directive 2001/83/EC * (This period may be extended for procedure under Articles 30 and 31 and by analogy also under Art. 36 and 37) CPMP-opinion and appeal mechanism The opinion of the CPMP may have negative implications for the applicant(s)/marketing Authorisation Holder(s), i.e., where the CPMP finds that: the application does not satisfy the criteria for authorisation, or the summary of the product characteristics proposed by the applicant(s)/marketing Authorisation Holder(s) in accordance with Article 11 of Directive 2001/83/EC should be amended, or the authorisation should be granted subject to conditions, considered essential for the safe and effective use of the medicinal product including pharmacovigilance, or a marketing authorisation should be suspended, varied or withdrawn, Once the opinion of the CPMP is adopted, the EMEA immediately informs the applicant(s)/marketing Authorisation Holder(s). Within 15 days of the receipt of the opinion, the applicant(s)/marketing Authorisation Holder(s) may notify EMEA in writing of his/their intention to appeal. In that case, he/they forward the detailed grounds for appeal to the EMEA within 60 days of receipt of the opinion. Within 60 days of receipt of the grounds for appeal, the CPMP considers whether its opinion 12

14 Community referral should be revised. In order to do so, it may appoint one of its members to act as Rapporteur (generally a different member than the one who had already acted as Rapporteur for this medicinal product) and Co-Rapporteur, where appropriate. The Rapporteur (and Co- Rapporteur where appropriate) is responsible for making an assessment of the grounds for appeal. Each of the grounds for appeal should be dealt with separately and a reasoned conclusion on all relevant points must be included in the assessment report. If no appeal is notified to the EMEA within 15 days, the opinion automatically becomes a final opinion. Timetable for the appeal-procedure Day 0 Receipt of CPMP s proposed opinion, acknowledged receipt by the applicant(s)/marketing Authorisation Holder(s) Until day 15 Applicant(s)/Marketing Authorisation Holder(s) shall notify EMEA of intention to appeal Until day 60 Applicant(s)/Marketing Authorisation Holder(s) forward to EMEA detailed grounds for appeal Within the CPMP considers the appeal and adopts final opinion following 60 days Final opinion Within 30 days of its adoption, the EMEA forwards the final opinion of the CPMP to the Member States, the Commission and applicant(s)/marketing Authorisation Holder(s) together with a report describing the assessment of the medicinal product and stating the reasons for its conclusions. The assessment report includes in an annex if the case may be - the conclusions reached on an appeal. In the event of an opinion in favour of granting, maintaining or varying a marketing authorisation for the medicinal product concerned, the following documents are annexed to the opinion: a) a draft SPC, b) any conditions considered essential for the safe and effective use of the medicinal product including pharmacovigilance. 7 Decision making procedure at Community level After the submission of the final opinion to the Commission, the Commission starts the Community decision-making procedure. This procedure is - in most aspects - the same as the procedure applicable in the centralised procedure (described in chapter 4 of the NTA). There is, however, one important difference: Community decisions following a Community referral are not only addressed to the applicant(s)/marketing Authorisation Holder(s) of the concerned product(s) but also addressed to the Member States concerned by the matter. Contrary to marketing authorisations issued in the centralised procedure which directly confer rights and obligations on the applicant(s)/marketing Authorisation Holder(s) without additional input from Member States, Community decisions taken following a Community referral request Member States to take action. 13

15 Community referral The concerned Member States are required to either grant, suspend, or withdraw the marketing authorisation, or vary the terms of the marketing authorisation as necessary to comply with the decision within 30 days of its notification and are required to inform the Commission and the CPMP of the measures taken. The decision is also transmitted to the Member States not involved in the procedure for information. There is also another difference. When the opinion of the CPMP is in favor of granting or maintaining a marketing authorisation, the documents annexed to the opinion are a draft SPC as refered to in Article 11 of Directive 2001/83/EC and, as the case may be, any condition affecting the authorisation i.e. considered essential for the safe and effective use of the medicinal product including pharmacovigilance. The decision of the Commission following the opinion of the CPMP does not include the package leaflet. Nevertheless, the package leaflet is requested to be in accordance with the SPC annexed to the decision of the Commission. 8 Consequences of a decision following a Community referral: Which Member States and which medicinal products are concerned by the referral? - The decision following a referral is applicable only to those specific medicinal products which have been the subject of the referral procedure and to those Member States involved in the procedure, as detailed in the Commission Decision. For instance, if during the course of an application for a generic medicinal product through the Mutual Recognition procedure, an Article 29 referral for public health reasons is triggered, the Marketing Authorisation Holder of the originator medicinal product is not concerned by this referral. Likewise, following an Article 29 referral procedure with respect to an originator medicinal product, the decision does not have legal consequences for the generic medicinal product. - A decision as a result of an Article 29 referral only affects the specific medicinal product and the Concerned Member States which were concerned by the Mutual Recognition Procedure, as detailed in the Commission Decision. If an Article 29 referral concerns a medicinal product for which there are marketing authorisations already granted in some Member States, in order to implement the harmonised SPC, a new Article 30 referral can be triggered for those existing marketing authorisations. Which actions should be taken by the Member States after the referral? - Community decisions taken following a Community referral request Member States involved in the referral procedure to comply with the Community decision within 30 days of its notification and to inform the Commission and the CPMP. The Marketing Authorisation Holder is urged to take appropriate steps necessary to allow the Member States to comply with the Community decision within 30 days after its notification. After a referral procedure with a positive opinion concerning the maintenance of a marketing authorisation, Member States concerned by the procedure must vary the terms of the marketing authorisation, as necessary, to comply with the decision of the Commission within 30 days after its notification. When the opinion is that a marketing authorisation must be suspended or withdrawn, Member States where the medicinal product is authorised shall suspend or withdraw the marketing 14

16 Community referral authorisation. This implies that when a referral procedure starts, the lists of Member States and medicinal products involved should be carefully examined. In those Member States not involved in the procedure, no direct action is required to be taken. If the opinion and the subsequent decision of the Commission is in favour to grant or maintain the marketing authorisation, the situation is the same for an Article 29, 30 or 31 referral as well as following an Article 31 or 35 concerning the suspension or withdrawal of a marketing authorisation of a medicinal product not authorised in those Member States. - However, in the case of a subsequent application for the same medicinal product, the evaluation must take into account the Community decision and Member States should grant or refuse the national marketing authorisations according to the terms of the Community decision unless there are risks to public health or issues which have not been previously considered. Any Member State or the Commission would as appropriate refer the new scientific issue to the CPMP in order to start a new referral procedure. The same applies in case where a marketing authorisation is pending for the medicinal product, which was the subject of the referral. The Member States must grant or refuse national marketing authorisations in accordance with the Community decision. The Community Decision is also transmitted to Member States not involved in the referral procedure so that they are informed and would be able to follow this Community Decision and take appropriate actions when needed (e.g subsequent submission in such Member State ). Can independent applications for marketing authorisation be launched when an Article 30, Article 31 or Articles 36 and 37 referral procedure is ongoing? - While an Article 30 or Article 31 referral procedure is ongoing, independent applications for marketing authorisation can be launched. Ongoing procedures can be finalised, even if the medicinal product is involved in the referral. Applications concerning medicinal products with the same active substance(s) can be launched and ongoing procedures for the same medicinal product can be finalised. For instance, if an Article 30 referral concerns the originator medicinal product, applications for generic medicinal products of this originator medicinal product may be submitted and ongoing procedures may be completed. Likewise, applications for variations to the originator can be launched and ongoing procedures can be finalised. If products with the same active substance(s) have been granted a marketing authorisation before or during an Article 30, Article 31 or Articles 36 and 37 referral procedure and have not been involved in the referral procedure and if these marketing authorisations are in contradiction with the outcome of the referral procedure, a new referral procedure can be triggered following the same articles. What about the harmonised SPC? - The opinion of the CPMP should answer and should be related to the question raised in the referral. But, following a referral procedure recommending the granting, maintenance or variation of (a) marketing authorisation(s), an SPC is annexed to the opinion of the CPMP and the subsequent Commission decision. This SPC is a harmonised SPC and is required to be implemented by all Member States concerned by the procedure. 15

17 Community referral It should be stressed that members of the CPMP are equally concerned by the question submitted to the CPMP. They take part in the evaluation procedure and the opinion independently of the Member State, which has designated the CPMP member, and of the situation of the medicinal product in the Member States. - The SPC shall contain the information as provided in Article 11 of Directive 2001/83/EC. The extent of the harmonisation of the SPC depends on the specific referral. In all cases: qualitative and quantitative composition in terms of the active substances, pharmaceutical form, pharmacological properties and clinical particulars should be harmonised. For the other parts of the SPC: tradename and pharmaceutical particulars, depending on the referral procedure there are some differences:. for an Article 29 referral the SPC is completely harmonised. Possible exceptions are only the tradenames and the names of the Marketing Authorisation Holders, as it is possible for the company to have different tradenames and different Marketing Authorisation Holders in the different Member States concerned;. for an Article 30 referral, 2 cases are possible:. when the referral is triggered by the Marketing Authorisation Holder in order to harmonise the SPC, all parts of the SPC are harmonised except, as above and for the same reasons, the tradenames and the names of the Marketing Authorisation Holders;. when the referral is triggered by a Member State or the Commission, it could be possible that in addition to the previous exceptions other parts of the SPC may be different. This could be the case for certain pharmaceutical particulars like the excipients and the shelf life. Concerning most particularly the excipients, as provided in Article 11 of Directive 2001/83/EC only the excipients knowledge of which is essential for proper administration of the medicinal product should be mentioned in the SPC. Therefore, the list of excipients can be left blank if it has not been dealt with in the procedure. The same applies for the shelf life or, as the case may be, for the special precautions for storage. The relevant information should be introduced nationally by the Member States when implementing the harmonised SPC. If necessary, for the opinion and the decision of the Commission, reference to an annex could be made in the SPC for instance for the tradenames, Marketing Authorisation Holders, packaging and packsizes;. for an Article 31 referral, as it can be triggered when the interests of the Community are involved, there are a lot of different situations which may have different consequences in terms of the harmonisation of the SPC. Nevertheless, in all cases, qualitative and quantitative composition in terms of the active substances, pharmaceutical form, pharmacological properties and clinical particulars should be harmonised. That means that even if a lot of medicinal products are concerned, for instance when an Article 31 is triggered for medicinal products containing the same active substance, for the opinion of the CPMP and the decision of the Commission, the SPCs should be prepared taking into account that qualitative and quantitative composition in terms of the active substances, pharmaceutical form, pharmacological properties and clinical particulars have to be harmonised. The other parts of the SPC, namely certain pharmaceutical particulars, could be left blank in the SPC annexed to the Community decision if they have not been dealt with during the procedure, for instance list of excipients, shelf life, special precautions for storage. The relevant information should 16

18 Community referral be introduced nationally by the Member States when implementing the harmonised SPC. If necessary, for the opinion and the decision of the Commission, reference to an annex could be made in the SPC for instance for the tradenames, Marketing Authorisation Holders, packaging and packsizes. What about subsequent applications occurring after finalisation of the referral? - Subsequent applications for the same particular medicinal product must use the results achieved (harmonised SPC) following the referral. After Articles 29, 30, 31 referrals subsequent applications for the same medicinal product must be submitted through the Mutual Recognition Procedure and must be mutually recognised in accordance with the relevant Commission decisions unless a new referral is triggered with respect to a potential new risk to public health. - In the case of Article 30 referral or Article 31 referral and where there is no Reference Member State, the applicant(s)/marketing Authorisation Holder(s) may choose the Reference Member State for the follow up of the procedure. - In case of an Article 31 referral, there may be a large number of applicants/marketing Authorisation Holders. In this case, more than one Reference Member State can be chosen but the harmonisation should be maintained. 17

19 Community referral ANNEX: Notification forms NOTIFICATION TO THE CPMP/EMEA SECRETARIAT OF A REFERRAL UNDER ARTICLE 29 OF DIRECTIVE 2001/83/EC. FAX NUMBER This notification is an official referral for arbitration to the CPMP made by the following Concerned Member State (CMS): Reference Member State: Concerned Member State(s): THIS NOTIFICATION IS COPIED TO APPLICANT / MARKETING AUTHORISATION HOLDER AND ALL MEMBER STATES Product Name, if appropriate, Strength and Pharmaceutical Form Marketing Authorisation Holder(s) Mutual Recognition procedure No. THE ABOVE-MENTIONED CMS CONSIDERS THAT THE AUTHORISATION OF THIS MEDICINAL PRODUCT MAY PRESENT A RISK TO PUBLIC HEALTH ON THE FOLLOWING GROUNDS (please provide a summary of background information and clearly precise the question that triggers the referral) (If this space is not sufficient, please summarise and add annex): Signed Date 18