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Questions and Answers on MRP & DCP after the EU Enlargement on 1 May 2004 & 1 January 2007

April 2004
Revision 2, December 2006

In this document, the term 'old MSs' means the 25 MSs of the EU pre-1 January 2007, as well as Norway, Iceland and Liechtenstein. The term 'new MSs' means the 2 new countries acceding to the EU on 1 January 2007.
This document was initially developed to address the enlargement of the EU on 1 May 2004 and has been revised, where appropriate, to consider also the accession of Romania and Bulgaria to the EU on 1 January 2007.

Other abbreviations used:

EU = European
UnionMA = Marketing Authorisation
MRP = Mutual Recognition Procedure
DCP = Decentralised Procedure
CMS = Concerned Member State
RMS = Reference Member State

Question 1 Where can guidance and recommendations in relation to MRP and EU enlargement be found?

They can be found in the document: “Phasing-in EU procedures: MRP and referrals” final version September 23rd, 2003. The document is published on this website (follow this link)

Question 2 When can the new MSs be included in an MRP or DCP?

New MSs can be included in an MRP or DCP from the date of Accession. 1st January 2007 is the first date that a Mutual Recognition or Decentralised procedure application can be submitted to RO and BG.

Question 3 Will RO and BG have equal rights with old MSs in terms of MRP and DCP?

RO and BG will have full rights as the old MSs as of 1st January 2007. This applies also to the MRP and DCP, where they can act as RMS or CMS.

Question 4 What is the derogation clause contained in the Accession Treaties of Cyprus, Lithuania, Malta, Poland and Slovenia, which acceded the EU on 1 May 2004 and where can information about it be found? Is there any derogation clause contained in the Accession Treaties of Romania and Bulgaria?

By way of derogation from the requirements of quality, safety and efficacy laid down in Directive 2001/83/EC, MAs for some pharmaceutical products in those countries which have a transitional period (Cyprus, Lithuania, Malta, Poland, Slovenia) issued under the law of the country in question prior to 1st May 2004, shall remain valid until they are renewed in compliance with the acquis and in accordance with the timeframe set out, or until the end of the derogation period, whichever is the earlier. Notwithstanding the provisions of Title III, Chapter 4, of the Directive, MAs covered by this derogation shall not benefit from Mutual Recognition in the Member States.
The lists of products and the set out timeframes are published in the appendix of annexes V to XIV of art. 24, title I (Temporary provisions) of the Act of Accession.
Bulgaria and Romania do not have any derogation clause in the Accession Treaties for medicinal products.

Question 5 Will the MA of Mutual Recognition products be recognised by the new MSs which are to join the EU in January 2007?

For products authorised in the old MSs via the MRP or DCP, a MA application within the framework of the Mutual Recognition Procedure has to be submitted to the national competent authorities of the new MSs.
Only Commission Decisions concerning products authorised by the centralised procedure will extend automatically to the territory of the new MSs which are to join the EU in January 2007.

Question 6 Can companies based in Norway, Iceland and Lichtenstein apply for MAs in new MSs?

Before enlargement national legislation applies. So, the competent authority of a new MS may ask/ advise (depends on current legislation of each country) the applicant to be based in the new MS or in the Community.
After enlargement, the common rules of Mutual Recognition will apply to all the Member States (old and new) and applications from companies based in Norway, Iceland and Lichtenstein will be accepted.

Question 7 What will happen with pending national applications in the Member States for products already approved/pending in another Member State at the date of Accession?

Articles 17(2) and 18 of Directive 2001/83/EC are applicable in this situation.
According to Article 17(2) of Directive 2001/83/EC, as amended, where a Member State (new or old) notes at the date of accession that another marketing authorisation application for the same medicinal product is being examined in another Member State, the Member State concerned shall decline to assess the application and advise the Applicant that Articles 27 to 39 of Directive 2001/83/EC apply.
The Member State, which has already started the examination, will normally be the future RMS.
See also Q&A 13 of the Questions and Answers on the implementation of the new legislation, published on the Heads of Medicines Agencies website http://heads.medagencies.org/mrfg/new_legislation/docs/QA_new_legislation.pdf
In the case of Article 18 where the same medicinal product is already authorised, via a national, mutual recognition or decentralised procedure, in a Member State at the date of accession the MS concerned shall reject the application, unless it was submitted via the Mutual Recognition Procedure and will inform the MS where the product has been authorised.
As stated under 3.2, chapter 2 of Volume 2A of NtA, differences between the SPC, PL and labelling approved in one MS and the SPC, PL and labelling submitted in another MS do not automatically prevent the latter from a MRP. If these differences have no therapeutic implications (no difference in the efficacy and safety profile), i.e. both products have the same qualitative and quantitative composition in active substances (i.e. the same strength) and the same pharmaceutical form, they have to be considered as being the same and the MRP has to be followed.
See also Q&A 14 of the Questions and Answers on the implementation of the new legislation, published on the Heads of Medicines Agencies website http://heads.medagencies.org/mrfg/new_legislation/docs/QA_new_legislation.pdf

Question 8 How should pending applications in old and new MSs on 1 January 2007 be progressed where there is also an authorised product on a transitional list? The particular situation is that the authorised medicinal product is subject to a derogation clause. Can the applicant continue with the pending national applications or should they select one of the MSs with a pending application and ask them to be RMS?

The authorised product on the transitional list cannot be the subject of an MRP until the dossier is in line with Directive 2001/83/EC. The authorisation of a medicinal product in an old MS with a transitional period and a dossier not in line with Directive 2001/83/EC, as amended, does not trigger Article 18 procedures.
Once compliance with Community law has been achieved, the authorisation does not rely anymore on the derogation and can benefit from mutual recognition.
On 1 January 2007, Article 17(2) of Directive 2001/83/EC, as amended applies, i.e. , the Member States where the applications are pending shall decline to assess the applications and advise the Applicant that Articles 27 to 39 of Directive 2001/83/EC apply.

Question 9 Is it possible for pending applications in new MSs on 1 January 2007 for medicinal products with a well-established use to continue national independent procedures?

According to the Commission communication on the Community marketing authorisation procedures for medicinal products 98/C 229/03, national independent procedures may still be followed in the case of a medicinal product with a well-established use (bibliographical applications), provided that the two following conditions are fulfilled:

The well-established use is based on data referring to an existing group of products with different SPCs in the Member States, and
No Community harmonisation of the use of the constituent(s) of the said product exists.

Community harmonisation of the use of the constituent exists if the constituent of the said product is the constituent:

Of a product which underwent the ex-concertation procedure within the scope of application of Directive 87/22/EEC,
Of a product involved in referral procedure under Article 30 of Directive 2001/83/EC, as amended, or
Involved in referral procedure under Article 31 of Directive 2001/83/EC, as amended.

Community harmonisation also exists in the case of a medicinal product authorised by MRP. Therefore, in these cases a product cannot be authorised by national independent procedure in further Member States.

Question 10 Where pending applications in new MSs are rejected after 1 January 2007, how is it intended to regulate the financial contribution of fees paid for these applications?

The fees for applications are a purely national issue, for which the competent authorities in the new MSs are solely responsible.

Question 11 What are the simplified CADREAC and nCADREAC procedures?

The so-called ‘simplified CADREAC and nCADREAC procedures’ have been adopted by CADREAC Annual Assembly, on April 2001 in Prague and on March 2004 in Bucharest, respectively. The purpose of the adopted documents is to describe a licensing procedure which can be used by any CADREAC drug regulatory authority, before the date of Accession, for granting an MA of a medicinal product, which has been authorised in the old MSs following the Mutual Recognition Procedure (MRP).
For further guidance see the document: ‘Procedure on the granting of Marketing Authorisations by new CADREAC (nCADREAC) drug regulatory authorities for medicinal products for human use already authorised in EU Member States following the mutual recognition procedure and the variations and renewals of such Marketing Authorisations’. The document can be found at the New CADREAC web site http://www.newcadreac.org/cadreac.html

Question 12 Is the use of the simplified nCADREAC procedure mandatory?

No, it is not mandatory either for the applicant or for the nCADREAC drug regulatory authority.
See the document: ‘Procedure on the granting of Marketing Authorisations by new CADREAC (nCADREAC) drug regulatory authorities for medicinal products for human use already authorised in EU Member States following the mutual recognition procedure and the variations and renewals of such Marketing Authorisations’, section “PRINCIPLES”. The document can be found at the New CADREAC web site http://www.newcadreac.org/simp_procedures.html

Question 13 How could an applicant benefit from having a product authorised in new MSs via the simplified CADREAC/nCADREAC procedure?

The principal benefit of having used the simplified CADREAC/nCADREAC procedure is the use of a shorter timeframe (30 days) in a repeat-use MRP if the MAH wishes to add a national MA granted before 1 January 2007 into an existing MRP and all MS involved in the procedure agree with the shorter timeframe.
Applicants are advised to discuss how to follow the new legislation with the RMS in advance of the submission of the MRP.
See also the document: “Position paper on repeat use of the mutual recognition procedure” Revision 5, February 2005, published in the Heads of Agencies website: http://heads.medagencies.org/mrfg/docs/inter/position.pdf

Question 14 Products approved in new MSs through the simplified CADREAC/nCADREAC procedure may have a different product name or have different pack sizes, or assembly and batch release sites from those approved in the old MSs. If these products are the subject of a shorter 30-day repeat use MRP, how will these differences be handled?

Different product names in different MSs are acceptable within an MRP. Additional pack sizes should be added to the MR-SPC either before or after the repeat-use procedure.
Additional assembly or batch-release sites may not be included in the repeat-use MRP but should be added by a Type IA variation after the procedure is finished. In relation to continuity of supply to the market, it should be noted that the current MA in the new MSs does not need to be withdrawn when a repeat-use MRP is started, so that batches may be supplied under that MA during the MRP. When the product is approved under the MRP, the original MA may either be withdrawn or the two MAs may have different names.

Question 15 Is it possible, within a repeat use MRP, to complete a variation to a product approved in the new MSs via the simplified CADREAC/nCADREAC procedure, if the variation is pending in the CMSs at the time of the MRP?

The dossier should include the pending variation application and this should be explained in the covering letter. Inclusion of pending variations may mean that it is not possible to complete the MRP according to the shortened 30-day procedure outlined in the Position paper on repeat use of the mutual-recognition procedure.

Question 16 If there are simplified nCADREAC procedures still pending in new MSs on 1 January 2007, is it possible to have a shorter 30-day administrative procedure for them without having to do a repeat-use procedure?

No, if the products are to be brought into MR, then a repeat-use MRP must be started.

Question 17 What is the documentation to be submitted for simplified MRP following CADREAC/nCADREAC procedures?

The principle of CADREAC/nCADREAC procedure was the submission of identical dossier and identical post-authorisation maintenance as in the MRP, as well as the submission of all assessment reports generated within MRP. Therefore the documentation to be submitted by the applicant can be limited to the following:

Application form
Declaration of MAH that the dossier already submitted in the new CMS is identical to the current dossier in RMS
Proposed dates for common MRP renewal and PSURs submissions
In the case that an application for MA variation of the product concerned is pending in the new CMS at the time of repeat use MRP, the explanation should be provided in the covering letter and acceptability of processing the repeat use procedure in 30 days should be pre-discussed with the new CMS
The RMS should send to the new CMSs the following:
Copy of current Product information
List of all variations and renewals approved in MRP for the product concerned
The common renewal date
In case of need the new CMS can request the RMS to send any missing variation report or an updated assessment report before the procedure can start.

Question 18 Can the shorter-timeframe MRP be used for products already harmonised in the old MSs, through referrals or through an MRP covering all EEA countries?

It is always possible to have a procedure which is shorter than 90 days if CMSs do not have any objections. In all cases, there must be an MR procedure and an application to the new MSs. It should be noted that following a referral, the product information may be harmonised but the dossiers not.
If the proposed product information (and the dossier) is the same as that (already harmonised) in the old MSs, this should be stated in the application, to inform the CMSs.

Question 19 If the dossier and product information of a product in new MSs is harmonised with the dossier and product information of an MR product, can a repeat-use MRP benefit from a shorter-30-day timetable? If there are differences, e.g., in pack sizes or manufacturing sites, can these be included in the application?

The MRP timetable can be shorter if all CMSs agree. Companies are advised to discuss their proposals with the RMS before submission of the application.
Any differences in the dossier should be handled as mentioned in the answer to question 14.

Question 20 Will it be possible to register ex-concertation products in new MSs through a repeat use MR procedure?

A repeat use is allowed if the ex-concertation product is still registered nationally in old MSs.

Question 21 If an ex-concertation product is already registered nationally in new MSs, would it be possible to use a repeat use to register the product through the MRP?

If the ex-concertation product is still registered nationally (through MRP) in old MSs, a repeat use procedure is allowed to register the product in new MSs through the MRP. However, it can remain as national MAs on the new MSs’ markets.
If MAH of the ex-concertation product has chosen to withdraw the national authorisations and to reapply for a Community marketing authorisation under Regulation 2309/93, the national marketing authorisations in new MSs become inapplicable.
Please refer to PERF Reflection paper on Phasing in EU procedures: MRP and referrals, September 2003, published on the Heads of Medicines Agencies website heads.medagencies.org.

Question 22 Will it be possible to export pharmaceuticals manufactured in the new MSs to old MSs immediately after they officially join the EU?

MA holders will be allowed to place medicinal products manufactured in the new MSs in other EU Member States provided that the product shall have a valid MA in the Member State where the product should be placed on the market and that the manufacturing site in question is covered by the MA.

Question 23 Will EU batch release requirements be the same in new MSs as in old MSs?

Yes. On Accession, the arrangements for batch release (Qualified Persons, manufacturing authorisation, etc) must be in place in each new MS.

Question 24 After repeat-use MRP to new MSs, will the product have the same common renewal date as it has in the old MSs?

Yes, the common renewal date already established for the product can be maintained.

Question 25 Is there an obligation to use the MRP or DCP for a line extension to a product initially approved through a national procedure in the new MSs, including products approved using the simplified CADREAC/nCADREAC procedure?

No, independent national procedures can be used for extensions of authorised medicinal products as far as no a priori harmonisation has been achieved.
For further guidance see the document: ‘Extension Applications in Mutual Recognition and Decentralised Procedures – Member States Recommendations, July 2006, published on the Heads of Medicines Agencies website http://heads.medagencies.org/mrfg/docs/rec/recext_app.pdf

Question 26 Can a product be the subject of an MRP if it is approved in Cyprus, Lithuania, Malta, Poland or Slovenia with a dossier that is not in line with the requirements of Directive 2001/83/EC, as amended and is therefore on a transitional list?

No, this is not possible. Only dossiers which meet EU requirements can be the subject of an MRP.

Question 27 How can an applicant combine into one MRP a MS with a transitional period and one without a transitional period?

The applicant should make a repeat-use MRP application into both CMSs, using the EU dossier already approved in the RMS.

Question 28 Can you confirm that the deadline for preparing/updating the assessment report is 90 days from the moment of official request made by the applicant?

For the steps to be taken in obtaining an assessment report, please consult Chapter 2 of Volume 2A of the Notice to Applicants. It should be noted that the request for an assessment report or an update of an assessment report occurs after any update of the dossier which may be necessary before starting an MRP. After the dossier has been updated, the applicant makes a formal request to the RMS for an (updated) assessment report, which is provided no later than 90 days after receipt of the request.

Question 29 Are the outcomes of all referrals (i.e. Articles 29, 30 and 31) binding on new MSs.

Referral decisions apply only to those MSs addressed in the Decision; they do not apply to MSs not addressed in the Decision nor to those MSs which later acceded to the EU. Please see PERF Reflection Paper on Phasing in EU procedures: MRP and Referrals, September 2003, published on the Heads of Medicines Agencies website http://heads.medagencies.org/.

Question 30 If companies wish to apply the outcome of SPC harmonisation voluntarily in new MSs, which procedure should they use, e.g., Type IB variation, number 46 or Type II variation?

Voluntary harmonisation is recommended. The procedure to be used for national marketing authorisations in new MSs depends on the national legislation for variations in each new MS.