cmd(v)/ifah-europe 2007 survey on the …product profile: of the 69 first and extension procedures,...

CMD(v)/IFAH-Europe 2007 SURVEY ON THE

MUTUAL RECOGNITION AND

DECENTRALISED PROCEDURES FOR

VETERINARY MEDICINAL PRODUCTS

June 2008

2007 MRP/DCP Survey Report June 2008

Table of Contents

EXECUTIVE SUMMARY................................................................................... 3

Mutual Recognition Procedures Summary Statistics ...................................... 5

Decentralised Procedures Summary Statistics................................................ 8

1. INTRODUCTION ......................................................................................... 9

2. METHOD.................................................................................................... 9

3. MUTUAL RECOGNITION PROCEDURE RESULTS ..........................................10

3.1 Application and product profiles ..........................................................10

3.2 Involvement of the Member States ......................................................10 3.2.1 Involvement as RMS ...........................................................................10 3.2.2 Involvement as CMS ...........................................................................11

3.3 The national assessment procedure .....................................................13

3.4 Validation ............................................................................................13

3.5 Number of questions ...........................................................................14 3.5.1 Number of questions per dossier .......................................................14 3.5.2 Number of questions per category and dossier part..........................14 3.5.3 Number of questions per CMS ...........................................................15

3.6 CMD(v) break‐out sessions...................................................................16

3.7 Final outcome: withdrawal, approval and referral rates .......................17

3.8 Functioning of the Mutual Recognition Procedure ...............................18 3.8.1 The view of the RMSs .........................................................................18 3.8.2 The view of the applicants..................................................................19

3.9 Impact of the 'new' Legislation.............................................................19 3.9.1 The view of the RMSs .........................................................................19 3.9.2 The view of the applicants..................................................................20

4. DECENTRALISED PROCEDURES RESULTS ....................................................20

4.1 Application and product profiles ..........................................................20

4.2 Involvement of the Member States ......................................................20 4.2.1 Involvement as RMS and reasons for choice ......................................20 4.2.2 Involvement as CMS and reasons for choice ......................................21

4.3 Validation ............................................................................................21

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4.4 Assessment step I.................................................................................21 4.4.1 Quality of the Applicants’ dossiers .....................................................21 4.4.2 List of Questions I (LoQ I)....................................................................22

4.5 Assessment Step II ...............................................................................23 4.5.1 Quality of the RMS’s draft Assessment Reports .................................23 4.5.2 List of Questions II (LoQ II) (n=29) ......................................................23 4.5.3 Applicants response to LoQ II and RMS assessment ..........................24

4.6 CMD(v) break‐out sessions...................................................................24

4.7 DCPs Final outcome: withdrawal, approval and referral rates ..............25

4.8 Functioning of the Decentralised Procedures .......................................25 4.8.1 The view of the RMSs .........................................................................25 4.8.2 The view of the applicants..................................................................26

4.9 General feedback to the DCP in comparison to the MRP ......................27

5. DISCUSSION..............................................................................................27

5.1 General discussion points.....................................................................27

5.2 CMD(v) discussion................................................................................28

5.3 EGGVP discussion.................................................................................30

5.4 IFAH‐Europe discussion ........................................................................31

6. CONCLUSION ............................................................................................32

ANNEX I: Tables ............................................................................................33

ANNEX II: List of acronyms............................................................................41

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CMD(v)/IFAH-Europe SURVEY ON THE MUTUAL RECOGNITION AND DECENTRALISED PROCEDURES

FOR VETERINARY MEDICINAL PRODUCTS IN 2007

EXECUTIVE SUMMARY

This is the ninth consecutive year that IFAH‐Europe1, and CMD(v)2 have monitored the functioning of the Mutual Recognition Procedure (MRP) for Veterinary Medicinal Products (VMPs). The survey was first initiated in 1998 by IFAH‐Europe the representative body of the European animal health industry (previously FEDESA), to become a joint exercise with CMD(v) (previously VMRFG) as from 1999. Furthermore, the 2007 report is the first to include information on the Decentralised Procedure (DCP), following its introduction in November 2005.

A total of 88 MRPs are included in this 2007 survey (cf. 95 in 2006 and 2005); they had either Day 90 (n=83) or Day 60 CMD(v) referral (n=5) falling in 2007. They involved 14 countries as Reference Member State (RMS) (cf. 12 in 2006 and 10 in 2005), 29 as Concerned MS (CMS) and 28 companies (cf. 35 in 2006 and 25 in 2005). The survey also includes 33 DCPs as follows: 3 with Day 210 in 2006, 27 in 2007 and 3 with Day 60 CMD(v) referral in 2007. These involved 7 countries as RMS, 26 as CMS and 18 applicants.

The RMSs completed 86 of the 88 MRP questionnaires and 29 of the 33 DCP questionnaires (out of the 4 missing DCP questionnaires, 3 were for the same product in 3 strengths). Applicants filled in 82 of the MRP questionnaires and all 33 of the DCP questionnaires. Thus, a comprehensive amount of data was gathered, which allowed the elaboration of this representative survey report.

Mutual Recognition Procedures

• Dossier profile: the 88 procedures included 19 repeat use dossiers (22%, cf. 10.5 % in 2006 and 27% in 2005), 1 line extension (1%; cf. 8.5% in 2006 and 2% in 2005) and 68 first procedures (77%; cf. 81% in 2006 and 70% in 2005) distributed as follows: ‐ 32 full standard procedures (Art. 12 of the Directive) (cf. 41 in 2006 and 31 in 2005), ‐ 23 generic (Art. 13 of the amended Directive) (cf. 25 in 2006 and 22 in 2005), ‐ 7 well established use (WEU) (Art. 13a of the Directive) (cf. 7 in 2006 and 9 in 2005), ‐ 3 fixed combination (Art. 13b of the Directive) (cf. 2 in 2006 and 4 in 2005), ‐ 2 informed consent (Art. 13c of the Directive) (cf. 2 in 2006 and 1 in 2005), ‐ 1 immunological under Art. 13d of the Directive (immunological with reduced field trials data) ‐ see also Figure 1.

Product profile: of the 69 first and extension procedures, 21 (30.5 %) were vaccines. This is broken down to 13 vaccines for livestock, 7 for companion animals and 1 for use in both livestock and companion animals. The 48 (69.5%) pharmaceuticals were distributed as follows: 27 for use in livestock, 20 in companion animals and 1 in both (see Figures 2 and 3). The 19 repeat use dossiers included 13 pharmaceuticals mainly for use in livestock.

Involvement of the Member States: 12 countries acted as RMS in the 69 non‐repeat use procedures (cf. 11 in 2006 and 8 in 2005). All 27 EU MSs plus Norway and Liechtenstein were CMSs; each was involved in 1 to 49 procedures. In the 19 repeat use procedures, 8 countries

1 IFAH‐Europe (International Federation for Animal Health – Europe) is the federation representing manufacturers of veterinary medicines, vaccines and other animal health products in Europe – see: http://www.ifaheurope.org/; known as FEDESA till January 2003. 2 CMD(v) is the Coordination group for Mutual Recognition and Decentralised procedures (veterinary) – see: http://www.hma.eu/cmdv.html; known as VMRFG till November 2005.

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http://www.ifaheurope.org/

http://www.hma.eu/cmdv.html


acted as RMS and all 27 EU MSs plus Norway were involved in between 1 to 11 CMS procedures (see Table 1).

Questions: for non‐repeat use procedures, the average number of questions per dossier was 72 (cf. 71 in 2006 and 70 in 2005) with most major questions to Parts II and IV (see Table 2); CMSs asked an average of 7.5 questions per dossier (cf. 8 in 2006 and 2005). For repeat‐use procedures, the average number of questions per dossier was 28 (cf. 8 in 2006 and 9 in 2005), with most major questions to Part II; CMSs asked an average of 5 questions per dossier (cf. 2 in 2006 and 2005).

CMS procedures and outcome: there were 703 first and extension CMS procedures (cf. 773 in 2006 and 616 in 2005); 655 (93.5%) were approved, while 16 (2%) were rejected at validation (cf. 0.5% in 2006 and 2% in 2005), 23 (3%) withdrawn and 9 (1.5%) referred. There were also 107 repeat use CMS procedures (cf. 38 in 2006 and 107 in 2005) of which 105 (98%) were approved and 2 (2%) were referred (see Table 3).

Referrals: 5 MRPs (4 first procedures and 1 repeat use) had issues referred to CMD(v); this corresponded to 11 CMS procedures (see Table 3). Out of these 5 procedures, 3 were solved at CMD(v) and 2 first procedures were taken to CVMP for arbitration. This aspect of the procedure is being assessed in more detail through separate surveys on the functioning of CMD(v) and CVMP referrals.

Functioning of the procedures: as in previous years, the overall functioning of the MRP was satisfactory; RMSs and companies however experienced recurring difficulties with some CMSs asking to comply with additional national requirements or failing to attend CMD(v) meetings. Reaching agreement on the SPC further remained an obstacle to the smooth running of the MRP.

Decentralised Procedures

Dossier profile: the 33 procedures were distributed as follows: 13 full dossiers, 17 generics, 1 WEU and 1 line extension (1 unknown; see Figure 4).

Product profile: of the 33 procedures, 9 (27%) were for vaccines split between companion animals (n=6) and livestock products (n=3); the 24 (73%) procedures for pharmaceuticals were split among products for livestock (n=10), companion animal (n=13) and 1 for use in both livestock and companion animals (see Figure 5).

Involvement of the Member States: 7 countries acted as RMS and 26 as CMS; they were the 27 EU MSs, except Bulgaria and Romania, plus Norway; all were involved in 3 to 28 CMS procedures (see Table 4).

Questions: List of Questions I (LoQ 1): there was an average of 76 questions per dossier, mostly on Quality Part II, where as LoQ II represented an average of 24 questions per dossier (see Table 5).

CMS procedures and outcome: there were 407 individual CMS procedures, which were all validated. Out of those, 398 (98%) procedures were approved, 6 (1.5%) were withdrawn and 3 (0.5%) were referred (see Table 6).

Referrals: 3 DCPs were referred to CMD(v); each procedure was referred by one individual CMS, which represented 0.5% of the 407 individual procedures. Out of these 3 procedures, 1 had the issue resolved at CMD(v) and the other 2 procedures were taken to CVMP for arbitration; both received a positive opinion.

Functioning of the procedures: RMSs and Applicants generally welcomed the DCP, though RMSs stressed the tight timelines at Step I. There also was an issue with regard to exchange of information on the reference product for generic applications, though this is not specific to DCP.

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Mutual Recognition Procedures Summary Statistics

Figure 1: MRP DOSSIER PROFILES SINCE 2003

Figures 2 and 3: PRODUCT PROFILES SINCE 2003 – 1st and line extension MRPs

In 2006 and 2007: 2 products were for use in both livestock and companion animals

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Table 1: INVOLVEMENT OF THE MEMBER STATES IN MRPs SINCE 2003

Survey Period 2003 1 2004 1 2005 1 2006 1 2007 2

1st and line extension 82 43 69 85 69

Number of countries as RMS 9 9 8 11 12

Number of countries as CMS 24 26 27 28 29

Total number of CMS procedures 839 466 616 773 703

Average CMSs per procedure 10 11 9 9 10

Repeat Use procedures 12 12 26 10 19

Number of countries as RMS 5 4 6 5 8

Number of countries as CMS 11 18 20 19 28

Total number of CMS procedures 27 32 107 38 107

Average CMSs per procedure 2 3 4 4 5

1: 22 EU Member States, i.e. include Cyprus, Czech Republic, Estonia, Hungary, Latvia, Malta and Slovakia who joined the EU on 1st May 2004, plus Norway, Iceland and Liechtenstein;

2: 29 EU Member States, i.e. include Bulgaria and Romania who joined the EU on 1st January 2007, plus Norway, Iceland and Liechtenstein.

Table 2: NUMBER OF QUESTIONS IN MRPs SINCE 2003

2006 2007Survey Period 2003 2004 2005

1st and line extension n=76 1 n=35 1 n=69 2 n=85 2 n=68 1

Average (and max.) questions per procedure 112 (296) 98 (267) 70 (274) 71 (216) 72 (287)

Average (and max.) questions per procedure and CMS 11 (27) 9 (23) 8 (25) 8 (78) 7.5 (76)

Repeat Use procedures n=9 1 n=10 1 n=26 2 n=10 2 n=18 1

Average (and max.) questions per procedure 20 (45) 12 (79) 9 (46) 8 (21) 28 (115)

Average (and max.) questions per procedure and CMS 9 (16) 5 (37) 2 (28) 2 (12) 5 (32)

1: survey sample, i.e. data only available for procedures where a questionnaire has been completed; 2: all procedures.

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Table 3: OUTCOME OF THE MRPs SINCE 2003

Survey Period 2003 1 2004 1 2005 1 2006 1 2007 2

1st and Line extension MRPs

Number of MR procedures 82 43 69 85 69

Number of referred MRPs 0 3 0 3 0 3 13 4 4 4

Number of CMS procedures 839 466 616 773 703

Non-validated CMS procedures 50 0 11 4 16

% non-validated 6% 0% 2% 0.5% 2%

Withdrawn CMS procedures 92 52 29 2 23

% withdrawn 11% 11% 5% 0.3% 3%

Referred CMS procedures 0 3 0 3 1 3 35 4 9 4

% referred 0% 0% 0% 4.5% 1.5%

Repeat Use MRPs

Number of MR procedures 12 12 26 10 19

Number of referred MRPs 0 3 0 3 0 3 1 4 1 4

Number of CMS procedures 27 32 107 38 107

Non-validated CMS procedures 0 0 0 0 0

% non-validated 0% 0% 0% 0% 0%

Withdrawn CMS procedures 7 1 2 0 0

% withdrawn 26% 3% 2% 0% 0%

Referred CMS procedures 0 3 0 3 0 3 1 4 2 4

% referred 0% 0% 0% 3% 2%

1: 22 EU Member States, i.e. include Cyprus, Czech Republic, Estonia, Hungary, Latvia, Malta and Slovakia who joined the EU on 1st May 2004, plus Norway, Iceland and Liechtenstein;

2: 29 EU Member States, i.e. include Bulgaria and Romania who joined the EU on 1st January 2007, plus Norway, Iceland and Liechtenstein;

3: CVMP referrals, according to Directive 2001/82; 4: CMD(v) automatic referrals (60 days), according to Directive 2001/82 as amended by Directive 2004/28.

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Decentralised Procedures Summary Statistics

FIGURE 4: DCP DOSSIER PROFILES IN 2006‐07

Figure 5: DCP PRODUCT PROFILES IN 2006‐07

Table 4: INVOLVEMENT OF THE MSs IN DCPs IN 2006‐07

Table 5: AVERAGE QUESTIONS IN 2006‐07

Number of DC procedures 33 1

Number of countries as RMS 7

Number of countries as CMS 26

Total number of CMS procedures 407

Average CMSs per procedure 12

List of Questions I (LoQ I) n=29 1

Average (and max.) LoQ I per d

76 (169)

List of Questions II (LoQ II) n=29 1

Average (and max.) LoQ II per d

24 (59)

Average (and max.) LoQ II per procedure and CMS 2 (37)

1: including 3 with Day 210 in 2006 1: survey sample, i.e. data only available for procedures where a questionnaire has been completed

Table 6: OUTCOME OF DCPs IN 2006‐07

Number of DC procedures 33 1

Number of referred DC Procedures 2 3

Number of CMS procedures 407

Non-validated CMS procedures 0

% non-validated 0%

Withdrawn CMS procedures 6

% withdrawn 1.5%

Referred CMS procedures 3

% referred 0.5%

1: including 3 with Day 210 in 2006

2: CMD(v) automatic referrals (60 days), according to Directive 2001/82 as amended by Directive 2004/28


THE 2007 MUTUAL RECOGNITION AND DECENTRALISED PROCEDURES FOR VETERINARY MEDICINAL PRODUCTS

1. INTRODUCTION

This is the tenth annual survey on the functioning of the Mutual Recognition Procedure (MRP) for Veterinary Medicinal Products (VMPs), which FEDESA, the representative body of the European animal health industry at the time (now IFAH‐Europe) initiated in 1998.

Back in 1997, the 15 EU Member States (MSs) established the Veterinary Mutual Recognition Facilitation Group (VMRFG) to coordinate the operation of the MRP. The procedure became compulsory a year later for companies wishing to register a product in more than one MS and the first

survey covered procedures from 1995 to 1998. All subsequent surveys as from 1999 became a joint collaboration between industry and the VMRFG; the reports are available on the HMA/CMD(v) website: http://www.hma.eu/169.html.

The regulatory environment has since significantly evolved with the EU enlargement to 25 MSs on 1st May 2004 and the introduction of the new pharmaceutical legislation, i.e. Directive 2001/82 as amended by Directive 2004/283, which was due for transposition by all MSs by 31st October 2005. This new legal framework brought in changes to the functioning of the MRP (see Chapter 4 of the amended Directive) and provided VMRFG with a legal entity (Article 31) and a new name, i.e. Co‐ordination Group for Mutual Recognition and Decentralised Procedures ‐ Veterinary (CMD(v)). It further introduced the Decentralised Procedure (DCP) and this 2007 survey is the first to monitor the functioning of the MRP together with the DCP. More recently, the EU further enlarged from 25 to 27 MSs with the entry of Bulgaria and Romania on 1st January 2007. A total of 30 countries, including the EEA countries, i.e. Iceland, Lichtenstein and Norway, are now involved with MRP and DCP.

In this new environment, IFAH‐Europe and CMD(v) feel it is particularly important to carry out this annual survey that encourages the dialogue between industry and national competent authorities and is seen as a valuable tool for monitoring the functioning of the MRP.

2. METHOD

Data collection procedure: on-line questionnaire

The on‐line questionnaire to collect feedback from industry and competent authorities was used for the fifth consecutive year (see: http://www.mrp.ifahsec.org/). Basic information, i.e. company name, RMS, product name, procedure number, date of Day 90/210 or Day 60 CMD(v) referral and outcome for each CMS, was provided by the CMD(v) secretariat, after being validated by the chair of the survey sub‐group, and entered by the IFAH‐Europe secretariat; RMSs and Applicants then completed their sections of the questionnaire. For the MRP, some sections of the 2006 questionnaire were reworded (minor changes). For the DCP, a questionnaire was elaborated jointly between IFAH‐Europe and CMD(v). Both MRP and DCP questionnaires are available at http://www.hma.eu/169.html for information. Dates ‘final translations sent’ and ‘licences issued’ are now recorded independently from the annual survey, since such data are difficult to collect by the time of closure of data entry, i.e. February.

Data collection, analysis and reporting

3 Consolidated Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products as amended by Directive 2004/28/EC

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http://www.hma.eu/169.html

http://www.mrp.ifahsec.org/

http://www.hma.eu/169.html

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-5/consol_2004/veterinary_code.pdf


The on‐line questionnaire enabled all data to be automatically extracted and tabulated. Data were also ‘cleaned’ to respect confidentiality by IFAH‐Europe and checked for accuracy and consistency by CMD(v).

The 14 Member States that acted as RMS for MRPs in 2007 completed the questionnaires for 86 of the 88 procedures fulfilling the survey inclusion criterion, i.e. Day 90 or Day 60 CMD(v) referral falling in 2007. The 28 companies involved completed 82 questionnaires; 4 of the 6 incomplete ones referred to 2 multiple strengths products.

In the 33 DCPs, RMSs completed 29 questionnaires (3 of the missing 4 were for a same product in 3 strengths) and Applicants filled in all of them.

The draft report was prepared by the IFAH‐Europe secretariat and sent for consultation to CMD(v) and IFAH‐Europe members. Contribution from EGGVP, the European Group for Generic Veterinary Products, was further sought for the discussion part of the report. The final report, once approved by CMD(v) and IFAH‐Europe, is sent to all participants and made available on the IFAH‐Europe and HMA websites.

3. MUTUAL RECOGNITION PROCEDURE RESULTS

3.1 Application and product profiles

=> First and extension procedures (n=69)

The 69 non‐repeat MRPs concluded in 2007 included 1 line extension for a livestock product.

For the fifth consecutive year, there was no procedure for products containing a new active substance (NAS); these are anyhow more likely to be submitted either via Decentralised Procedure (Article 32.3 of the Directive) or Centralised Procedure (Regulation 726/2004).

Non‐standard applications, i.e. generic (23), WEU (7), fixed combination (3) and informed consent (2) represented 53% of the first procedures (36/68) and were solely for pharmaceutical products, except for one biological product submitted under Article 13d, i.e. immunological with reduced field trials data. The first applications were mainly for livestock products (39/68 ‐ 57%) split between pharmaceuticals (n=27) and vaccines (n=12) (see Tables 1 and 2 in Annex I).

=> Repeat use procedures (n=19)

The 19 repeat use procedures represented 22% of all procedures in 2007. They included 13 pharmaceutical products (of which 8 were generics) split between livestock (n=9) and companion animals (n=4); the 6 vaccines were for use in livestock (n=4) and companion animals (n=2).

3.2 Involvement of the Member States

3.2.1 Involvement as RMS

=> First and extension procedures (n= 69)

In 2007, 12 MSs were involved as RMS as follows: UK acted as RMS the most with 27 procedures (39%), followed by Ireland with 10 procedures (14.5%), Germany with 8 (11.5%), France with 7 (10%), Spain with 6 (8.5%), Sweden with 3 (4.5%), Hungary and Italy with 2 (3%) and Austria, Finland, Slovakia and Portugal with 1 (1.5%) procedure each. Austria and Portugal acted as RMS for the first time (see Figure 1 overleaf and Table 3 in Annex I).

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There were 8 countries involved as RMS in 2007, namely: Ireland with 6 procedures, Germany and France with 3 procedures each, Sweden and the UK with 2 procedures, the Czech Republic, Finland and the Netherlands with one procedure each (see Table 4 in Annex I).

3.2.2 Involvement as CMS


All 27 EU MSs plus Liechtenstein and Norway, i.e. a total of 29 countries were involved as CMS (cf. 28 in 2006 and 27 in 2005). Iceland was not included in any of the procedures. The CMS involved in most procedures was Spain with 49 procedures, followed by Portugal with 45. The 69 first and extension procedures represented a total of 703 involvements as CMS (cf. 773 in 2006 and 616 in 2005), including 16 rejected at validation (see 3.4 Validation for details). The average number of procedures per CMS was 24 (cf. 26 in 2006 and 23 in 2005). Applications were, on average, submitted in 10 MSs ranging from 1 to 23 (cf. 9 in 2006 and 2005). The involvement of each MS as CMS in the 69 procedures is summarised in Table 5 in Annex I. Table 6 further gives a breakdown of the average number of CMSs for full and generic dossiers.

The involvement as ‘RMS and CMS in 2007’ and ‘CMS since 2005’ are given in Figures 1 and 2 below respectively.

Figure 1: RMSs and CMSs in first and extension MRPs in 2007

Figure 2: CMSs in first and extension MRPs since 2005

The 15 EU MSs May 2004 10 MSs Jan. 2007 2 new MSs

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28 countries were involved as CMS in the 19 repeat use procedures, which gave a total of 107 CMS procedures. The average number of procedures per CMS was 4 (cf. 2 in 2006 and 5 in 2005) and involvement ranged from 1 procedure for 6 MSs, up to 10 procedures for the Czech Republic and 11 for Poland (see Table 7 in Annex I).

The involvements as ‘RMS and CMS in 2007’ and ‘as CMS since 2005’ are given in Figures 3 and 4 below respectively.

Figure 3: RMSs and CMSs in repeat use MRPs in 2007

Figure 4: CMSs in repeat use MRPs since 2005

The 15 EU MSs May 2004 10 MSs Jan. 2007 2 new MSs

3.2.3 Reasons for choice/exclusion of CMSs


As in previous years, commercial and marketing interest motivated the choice of the CMSs for more than 60% of the applicants. Some applicants also stated that national legislative requirements limited their choices of CMSs.

=> Repeat use procedures (n= 19)

Expansion to new markets was the main reason for the choice of CMSs. Two applicants further commented that the procedures were conducted in order to harmonise the national Marketing Authorisations.

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Amongst the 19 repeat‐use MRPs, 13 were submitted to register the product in new MSs, i.e. none of the CMSs chosen had been withdrawn from a past application; the other 6 repeat use MRPs involved a combination of both new CMSs and some where withdrawals had previously occurred.

3.3 The national assessment procedure

3.3.1 Quality of the Applicant's dossier


RMSs rated the applicants’ dossiers from ‘below par’ 1.5% (cf. 5% in 2006), to ‘acceptable’ 33% (cf. 22% in 2006), ‘good’ 57% (cf. 69% in 2006) up to ‘excellent’ 7% (cf. 4% in 2006); the remaining 1.5% did not answer this question. No application was rated as 'poor' (see Table 8 in Annex I). The relevant RMS reported that the dossier rated 'below par' had not been updated with all the relevant information for starting the MRP (an additional efficacy study report was missing).


The dossiers had been well prepared and rated ‘acceptable’ (18%), ‘good’ (70%) or ‘excellent’ (12%).

3.3.2 Quality of the RMS Assessment Report


Applicants rated the RMS Assessment Reports (AR) from ‘acceptable’ 10% (cf. 1% in 2006), to ‘good’ 53.5% (cf. 71% in 2006) up to ‘excellent’ 27.5% (cf. 15% 2006). The remaining 9% did not answer that question (see Table 8 in Annex I).


Applicants noted that the RMS Assessment Reports had been very well prepared, rating their majority either as good (63%) or excellent (26%); 5.5% were acceptable; the other 5.5% did not answer the question.

3.4 Validation


Based on the information gathered from the questionnaires, it appears that 16 (2%) of the 703 CMS procedures were not validated (cf. 0.5% in 2006 and 2% in 2005). It must however be stressed that non validated procedures are not necessarily all recorded in the survey, i.e. this figure could be higher. ‐ In 2 Informed Consent and 1 generic applications, 1 out of 3, 6 out of 9 and 1 out of 6 CMSs did not validate the dossier respectively; the reason was because the CMSs did not accept the European Reference product.

‐ A generic application was rejected by 1 of the 7 CMSs due to lack of data. ‐ One vaccine dossier was not validated in 6 of the 22 CMSs due to divergent views over the use of diluents.

‐ In another vaccine application, 1 of the 18 CMSs did not validate as it did not accept the GMP documentation provided by one laboratory carrying out the testing on the finished product.

Furthermore, some delays at validation (37 and 60 days respectively) were recorded in 2 cases; one was due to the ‘new’ legislation not yet being part of the EEA agreement, hence the Norwegian national legislation did not allow the European Reference Product concept at the time of submission.


All repeat use procedures were validated, as it has been the case since 2003.

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3.5 Number of questions

The number of questions was available for 68 of the 69 ‘first and extension MRPs’ and 18 of the 19 repeat use MRPs.

3.5.1 Number of questions per dossier


In 2007, applicants received an average of 72 questions per dossier (cf. 71 in 2006 and 70 in 2005). It ranged from no questions in 2 applications (both generic MRPs involving 1 CMS) up to 287 in a vaccine dossier with 23 CMSs (cf. 216 in 2006 and 274 in 2005).

Figure 5: Range of questions asked in first and extension MRPs since 2004

Most procedures (n=31; 45.5%) received between 0 and 50 questions (cf. 42.5% in 2006 and 42% in 2005); 17 applications (25%) had between 51 and 100 questions; 14 from 101 to 150 (20.5%); the remaining 6 procedures had more than 150 questions (see Figure 5 and Table 9 in Annex I).


Applicants were asked an average of 28 questions per dossier (cf. 8 in 2006 and 9 in 2005) ranging from 0 in 1 procedure up to 115 in a pharmaceutical application involving 22 CMSs.

3.5.2 Number of questions per category and dossier part


Figure 6: Distribution of questions by category in first and extension MRPs in 2007

The average number of questions per dossier was 12 minor, 20 major and 39 on ‘SPC, Labelling and Package Leaflet’; it corresponded to an overall distribution of 16% of minor questions, 29% of major and 55% of product literature (PLit) related questions (see Figure 6 and Table 10 in Annex I).

As in previous years, most major questions related to the Quality Part II (36% for pharmaceuticals and 48% for vaccines) and Efficacy Part IV of the dossiers (39% for pharmaceuticals and 26% for vaccines) (see Figures 7 and 8 below and Table 11 in Annex I)

Figures 7 and 8: Distribution of major questions by dossier part in first and extension MRPs in 2007



Fifty three percent (53%) of questions to repeat use dossiers related to the Product Literature (cf. 63% in 2006 and 41% in 2005) and major questions decreased down to 20% (cf. 26% in 2006 and 45% in 2005) with a focus on Quality Part II of the dossier (see Figures 9 and 10 below). Figure 9: Distribution of questions by category in repeat use MRPs in 2007

Figure 10: Distribution of major questions by dossier part in repeat use MRPs in 2007

3.5.3 Number of questions per CMS


The overall average number of questions to a dossier was 7 per CMS (cf. 8 in 2006 and 2005), ranging from 0 for 8 countries (Cyprus, Estonia, Lithuania, Luxemburg, Latvia, Malta and Romania) to 30 for France (see Table 12 in Annex I). When looking at the average number of questions per CMS in relation to the type of dossier, WEU received the most questions in 2007 (see Table 13 in Annex I).

As a question can trigger a related SPC one, the number of non‐SPC, i.e. Parts I to IV, and SPC questions were looked at separately for each country.

Parts I to IV questions (minor and major): the average number of questions per CMS varied between 0 and 1 for Austria, Bulgaria, Cyprus, Estonia, Greece, Lithuania, Latvia, Luxemburg, Malta, Romania, Slovenia and Slovakia; it reached 21 for France that remained the CMS asking the most questions

SPC, labelling and package leaflet related (PLit) questions: the average number of questions per CMS varied between 0 and 1 for Austria, Belgium, Bulgaria, Cyprus, Estonia, Greece, Lithuania, Latvia, Luxemburg, Malta, Romania, Slovenia and Slovakia; the maximum was 11 for Ireland.

See Figures 11 and 12 below and Table 14 in Annex I.

Figure 11: Average Parts I to IV questions per CMS in first and extension MRPs since 2004

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Figure 12: Average SPC related questions* per CMS in first and extension MRPs since 2004

* since 2006, these include questions on ‘Labelling and Package leaflet’


The overall average number of questions to a repeat use dossier was 5 per CMS (cf. 2 in 2006 and 2005); it ranged from 0 to 32 for Spain. The countries which asked the highest average number of questions per dossier was Finland (n=25) (cf. 12 by Denmark and UK in 2006).

3.6 CMD(v) break-out sessions


In order to solve the objections raised by the CMSs, a break‐out session took place in 41 (59%) procedures (cf. 39% in 2006 and 68% in 2005), including 23 pharmaceuticals (14 were generics which corresponded to 60% of all generic procedures) and 18 vaccines.

RMSs’ views RMS rated 33 of the 41 break‐out sessions as useful (80%; cf. 88% in 2006 and 72% in 2005) and 5 as not so useful (3 RMSs did not answer this question). The discussion was attended by all CMSs in 29 of the 41 procedures4. Some difficulties occurred in 4 of the sessions where one of the CMSs raising major questions did not attend (see Table 15 in Annex I). In 2 vaccine MRPs, there was a discussion over: ‐ The request for country of origin of starting materials; ‐ The vaccination age and schedule. In a generic application, as there was a simultaneous procedure for another generic with the same active substance, some CMSs involved in both applications wished to harmonise the SPCs of both products.

4 Of the 12 sessions not attended by all CMSs, 2 products were discussed in 2 of them, i.e. there were in fact 8 sessions not attending by all objecting CMSs.

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Figure 13: Overview of areas discussed in the 2006 and 2007 at CMD(v) break‐out sessions

Applicants’ views Applicants were immediately informed of the outcome of 35 of the 41 break‐out sessions. In the end, changes to the SPC were made in 7 procedures, including changes to (n=1) or loss of indications (n=4). In a procedure for a biological, a minority of the CMSs insisted that 4 of the 5 proposed target species be taken off the SPC and that the remaining claims be reduced; in the end, the applicant decided to withdraw its application from the RMS and all 23 CMSs. Finally, 4 of the 41 MRPs where a break‐out session took place, were referred to CMD(v) (see Table 15 in Annex I).


RMSs’ views A breakout session took place in 3 of the 19 repeat use procedures and all were rated as useful, though only 1 was attended by all objecting CMSs.

Applicants’ views All applicants were kept informed of the outcome but not all problems were solved and the SPC had to be amended in 2 procedures; the other procedure was referred to CMD(v).

3.7 Final outcome: withdrawal, approval and referral rates


Withdrawals A full application was withdrawn from all 23 CMSs in 2007. This corresponded to 3% of withdrawals from the 702 1st and extension CMS procedures (cf. 0.3% in 2006 and 3% in 2005). By withdrawing in all CMSs and the RMS, the matter was not taken forward to arbitration.

Approvals In 2007, 4 MSs (Czech Republic, Malta, Slovakia and Liechtenstein) had 100% approval rate; Austria, Belgium, Ireland, Luxemburg, Netherland, Poland and Portugal followed with over 95% approval. The CMSs with the lowest rate were France and the UK with 86% and 84% respectively5.

Referrals (inclusion criteria: Day 60 CMD(v) referral fell in 2007) A total of 4 first procedures were referred to CMD(v) by Germany, France, Italy, Sweden and the UK. This corresponded to 9 CMS procedures (1.5%). All were pharmaceuticals for use in livestock and included 1 full dossier, 1 WEU and 2 generic applications. Two of them were solved at CMD(v) and the other 2 were referred to CVMP. Note: a separate survey on CMD(v) and CVMP referrals is being carried out.

5 Note: these approval rates take into consideration the ‘non‐validation’ rate – see Figure 14 above and Table 16 in Annex I for details

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Figure 14: Outcome per CMS in the first and extension MRPs in 2007


Most repeat use procedures were approved; only 1 application was referred to CMD(v) by Denmark and Norway; it represented 2% of the 107 CMS procedures and the issue was solved at the CMD(v) 60 day step.

3.8 Functioning of the Mutual Recognition Procedure

3.8.1 The view of the RMSs

RMSs rated the 88 procedures as either ‘poor’ 2% (cf. 1% in 2006), ‘below par’ 2% (cf. 2% in 2006), ‘acceptable’ 20.5% (cf. 25% in 2006), ‘good’ 60% (cf. 65% in 2006) or ‘excellent’ 13% (cf. 5% in 2006); 2.5% did not answer this question.

Functioning with the Applicants Major good points On most procedures, the positive feedback generally referred to good cooperation and communication with the applicant and respect of timelines. Dossier presentation was also a positive aspect, e.g. good expert reports, together with reliability for attempting to solve issues.

Reported main difficulties Despite few specific issues, there were no real major problems encountered with applicants. The main issue with applicants were: ‐ Lack of transparency; relevant information not provided in the initial phase of the procedure; ‐ Not respecting deadlines for providing answers to questions; ‐ Direct discussion with CMS, which prevented the RMS from acting more effectively in resolving differences.

No major problems were encountered in the repeat use procedures.

Functioning with the CMSs Major good points The most quoted good point addressed by RMSs was the good communication with constructive discussion of outstanding issues. Mutual recognition and harmonisation spirit was also acknowledged.

Reported main difficulties The RMSs reported that non‐attendance at the CMD(v) meeting and raising issues late in the procedure were major concerns. Other concerns regarded some CMSs encouraging more discussion than necessary on certain points, poor and difficult communication, CMSs corresponding directly with

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the applicant; in another procedure, a CMS had no interest in reaching a positive outcome due to the lack of interest in the product for its market.

3.8.2 The view of the applicants

Applicants were generally pleased with most aspects of the procedures, which were rated ‘acceptable’ 11.5% (cf. 8.5% in 2006), ‘good’ 53.5% (cf. 49% in 2005) or ‘excellent’ 25% (cf. 24% in 2005). The remaining 9% did not answer the question and 1% were rated as ‘poor’ in 2007.

Functioning with the Reference Member States

Major good points The Applicants’ feedback mainly acknowledged the good cooperation and communication with prompt and clear responses, efficiency in resolving issues between applicant and CMSs, pragmatic approach, availability and willingness to advice and accuracy in following deadlines.

Reported main difficulties Very few difficulties were reported; only 4 applicants stressed the unavailability of the RMS contact persons during critical phases of the MRPs.

Functioning with the CMSs Major good points The major good points were good communication, cooperation and accuracy in following deadlines. Other points related to clear and reasonable questions and mutual recognition spirit.

Reported main difficulties Difficulties were reported in a limited number of MRPs, which included: - Validation issue with several MSs, - High number of questions, - Lack of Mutual Recognition, - Unavailability of the assessors, - Non‐attendance at the CMD(v) meeting, - Unjustified referrals and - Delay in granting the Marketing Authorisation.

An overview of the rating of procedures by RMS and Applicants is given in Table 17.

3.9 Impact of the 'new' Legislation

The ‘new’ legislation had been in application for two years and RMSs and applicants experienced fewer difficulties than in 2006.


Increase in workload and number of CMSs questions: this was accounted for by the inclusion in the dossier of a ‘Detailed Description of the Pharmacovigilance System’ and of ‘Product literature and labelling’.

Automatic arbitration: especially where only 1 CMS objects, 2 RMSs commented that the Applicant should be able to withdraw without referral being initiated.

Reference product and generic applications: the new legislation has facilitated the registration of generics, especially where the concept of 'European reference product' applies. This concept however created difficulties on other occasions:

- In 1 procedure, reference to the European Reference product led to a referral as the concept of ‘exchange of necessary information’ was not applied similarly by all MSs.

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- CMSs expressed their own views on harmonisation of SPC with that of similar products authorised on their territory.


Harmonisation of labelling and Package Leaflet: in 6 procedures, this led to increased workload with limited mutual recognition spirit; on the other hand, this was described as a key aspect to speed up the process in 1 procedure.

Guideline6 on Potential serious risk to human or animal health or the environment: the GL is of limited value as it only mentions reasons which are not considered to be a potential serious risk. Furthermore, CMD(v) has no mandate to decide on what is considered to be a potential serious risk; also where it is known from Day 90 that no agreement will be reached and that the issue will have to be referred to CVMP, the CMD(v) 60 days phase appears to be a waste of regulators and companies’ valuable time.

Automatic arbitration: this delays (6 months) the granting of an authorisation; also in some cases where the matter was referred to CVMP, non‐objecting CMSs still refuse to deliver an authorisation.

Generic applications: the European Reference Product concept allows smoother registration of generics in CMSs where the reference product does not exist.

4. DECENTRALISED PROCEDURES RESULTS

4.1 Application and product profiles

There were 33 Decentralised Procedures (DCPs) in 2006‐07; though 2 of them were eligible for the Centralised Procedure, one applicant decided to use the DCP to select a limited number of CMSs (n=4), the other wished to have a first experience with this new procedure as introduced by Directive 2004/28.

The 33 DCPs included 13 full standard applications, none of which contained a new active substance (NAS). The non‐standard applications, i.e. 1 WEU, 1 Line extension and 17 generics represented 58% of the procedures (19/33) and were solely for pharmaceutical products. Most DCPs (73%) were for pharmaceutical products for use in companion animals (n=13), livestock (n=10) or both (n=1). The remaining 27% of DCPs were for biological products distributed as follows: 6 for use in companion animals and 3 in livestock (see Tables 18 and 19 in Annex I).

4.2 Involvement of the Member States

4.2.1 Involvement as RMS and reasons for choice

There were 7 MSs involved as RMS in DCPs as follows: UK acted as RMS the most with 12 procedures (36.5%), followed by France with 8 (24.5%), Ireland with 7 (21%), the Netherlands and Germany with 2 each (6%) and Denmark and Spain with 1 each (3%) (see Table 20 in Annex I).

The most quoted reason for choice of RMS was its previous involvement in licensing similar products or products containing the same active substance. The second most quoted reason was the applicants’ good previous experience with the MS. Other applicants relied on the country’s availability to start the procedure in a reasonable time.

6 Guideline on the definition of a potential serious risk to human or animal health or for the environment in the context of Article 33(1) and (2) of Directive 2001/82/EC (Official Journal C 132, 7/6/2006 p. 32 ‐ 35) and Annex

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http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-6/newdoc/2006_C_132_08_en.pdf

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-6/newdoc/ser_risk_annex_v.pdf


4.2.2 Involvement as CMS and reasons for choice

A total of 26 countries were involved as CMS; they were the 27 EU MSs, except Bulgaria and Romania, plus Norway. Spain was involved in the most DCPs with 28 procedures, followed by Italy with 26. The 33 DCPs represented a total of 407 involvements as CMS. Each application involved an average of 12 CMSs ranging from 2 to 22 and each CMS was involved in an average of 16 procedures (see Table 21).

More than 70% of the applicants made their CMS choice based on market and commercial reasons; in a line extension application, the choice of CMSs was driven by those MSs where the original product was already authorised. Two applicants stated that exclusion of certain MSs was due to national regulations and other two had to exclude some MSs where the reference product was still under data protection.

The involvement of each MS in the DCPs is summarised in Figure 15.

Figure 15: Involvement as RMS and CMS in DCPs in 2006‐07

4.3 Validation

Based on the information gathered from the questionnaires, it appears that all 407 CMS procedures were validated. It must however be stressed that this is not accurately recorded in the survey, i.e. there may have been procedures that failed validation.

Some problems were also reported at this stage of the procedure by some applicants: ‐ MSs issues with the PhV related information; ‐ Issue with national requirements in 1 CMS; these were resolved in the end; ‐ Request for additional copies of Part 1 in the national language in another CMS;

The clock start was even delayed in 2 cases by 14 and 40 days respectively; in the first case, 1 CMS required SPC translation; in the other procedure, 1 CMS required Part I translation, another asked for packaging mock ups.

4.4 Assessment step I

4.4.1 Quality of the Applicants’ dossiers

RMSs reported that the Applicants submitted their dossier in time for the agreed start of step I in 29 of the procedures (4 did not reply). RMSs further rated the applicants’ dossiers from ‘acceptable’ (12%) to ‘good’ (70%); no dossiers were rated as ‘poor’ or ‘below par’; 18% did not answer the question (see Table 22 in Annex I).

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4.4.2 List of Questions I (LoQ I)

The number of LoQ I was collected as follows: sum of all CMSs’ questions on Part I, Part II, Part III, Part IV and ‘SPC, Labelling & PL’.

RMSs’ views: RMSs rated the CMSs’ contribution to the questions most helpful; some questions were left out in 18 cases; 5 RMSs did not answer this section of the questionnaire.

Number of LoQ I per dossier (n=29) Figure 16Applicants received an average of 76 questions

per dossier, ranging from 24 questions in an application for a biological product up to 169 for a generic. The majority of the procedures (58%) received between 50 and 100 questions; 21% received less than 50 questions and the other 21% received more than 100 questions per dossier (see Figure 16).

: Range of LoQ I in DCPs in 2006‐07

As for MRPs, a question can trigger a related SPC one and the number of non‐SPC, i.e. Parts I to IV, and Product Literature questions were looked at separately. There was an average of 51 LoQ I to Parts I to IV and 24 to ‘SPC, Labelling and Package Leaflet’ (see Tables 23 and 24 in Annex I).

For pharmaceuticals, the average was 57 (65%) Parts I to IV and 31 (35%) Product Literature related questions; for biologicals, the split was 40 (81%) and 10 (19%) respectively. Parts I to IV mainly were on Quality Part II for pharmaceuticals (68%) and vaccines (47%) (see Figures 17, 18 and 19 below).

Figure 17: Distribution of LoQ I by category in DCPs

Figures 18 and 19: Distribution of LoQ I by dossier Parts I to IV in DCPs

Applicants’ responses to LoQ I: some applicants acknowledged good communication with the RMS and a well prepared LoQ I which was helpful when preparing answers. For other applicants, many questions were outside the scope of the type of the application and/or a relatively large list of questions made it a big job to deal with. In a generic application for instance, there were several questions on efficacy and ecotoxicity for a product already established in several EU MSs; in other 3


generic applications, there were many questions linked to the harmonisation of the SPC of the reference product.

Clock‐stop: in 14 of (42%) of the procedures, the initial clock‐stop was of less than 3 months. Applicants asked for an extension to the 3 months clock‐stop to prepare their answer to LoQ I in 9 procedures; this was granted in all cases; it was not known what happened in the other 10 procedures.

4.5 Assessment Step II

4.5.1 Quality of the RMS’s draft Assessment Reports

Applicants that commented on the quality of the draft Assessment Report acknowledged very good quality of the RMS’s evaluation and some RMSs conducting generic applications had followed the approved SPCs from the reference product. Applicants rated the RMS draft Assessment Reports from ‘acceptable’ (3%), to ‘good’ (85%) up to ‘excellent’ (3%); the remaining 9% did not answer that question (see Table 22 in Annex I).

4.5.2 List of Questions II (LoQ II) (n=29)

By RMS: in 9 procedures, RMSs asked questions on Part II and SPC; the questionnaire had not been designed to record accurately this information and no more information on ‘LoQ II by RMS’ is therefore available.

Per dossier: in 2007, applicants received an average of 24 questions per dossier. It ranged from 0 in a generic dossier involving 7 MSs to 59 in a generic dossier with 13 CMSs. Most procedures (n=27; 93% received between 0 and 50 questions.

Per Category and dossier part: the average number of LoQ II per dossier was 2 ‘Points for clarification’, 7 ‘Parts II to IV’ and 15 ‘SPC, Labelling and Package Leaflet’ questions; this corresponded to an overall distribution of 10% ‘Points for clarification’, 30% Parts II to IV and 60% SPC related questions (see Tables 25 and 26 in Annex I). For pharmaceuticals, most questions related to the Quality Part II (65%) as accounted for by the high number of generic DCPs; there was a more even distribution between Parts II, III and IV for biologicals (see Figures 20 and 21 below).

Figures 20 and 21: Distribution of LoQ II by dossier Parts II to IV

Per CMS: 9 countries raised no questions; Germany and Spain (n=6) and France (n=7) were the CMSs asking the most LoQ II (see Figure 22 overleaf and Table 27 in Annex I).

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Figures 22: Average LoQ II per CMS

Figure 23 further shows the relation between the average number of LoQ I and LoQ II per type of dossier, where WEU received the most LoQ I (n=133) and full applications the most LoQ II (n=31).

Figure 23

4.5.3 Applicants response to LoQ II and RMS assessment

Since a limited number of issues had been carried forward to step II, most applicants submitted comprehensive and complete responses that were rated ‘acceptable’ 12%, to ‘good’ 67%, up to ‘excellent’ 3%. No procedures were rated ‘poor’ or ‘bellow par’; there was no answer to that question in 18% of the questionnaires. The quality of RMS final assessment was rated by 88% of the applicants as ‘good’ and the remaining 12% did not answer to that question (see Table 22).

4.6 CMD(v) break-out sessions

In order to resolve the objections raised by the CMSs, a break‐out session took place in 14 (42%) of the 33 procedures; 9 were on immunological applications, 5 on pharmaceuticals, including 2 generics; 6 did not answer the question, i.e. it is not known whether a discussion took place or not.

RMSs’ views RMS rated 11 (79%) of the 14 break‐out sessions as useful, though no serious risk issues were discussed in 3 of them. The discussion was attended by all objecting CMSs in 8 of the 14 procedures and absence was a problem in 2 of the 6 sessions where CMSs were not present. The issues discussed at break‐out sessions covered the following areas:

Issues discussed Number of sessions Safety 2 (including 1 ERA) Quality 2 Residues / WP 1 Efficacy 2 SPC 2

Applicants’ views Applicants were immediately informed of the outcome of 12 of the 14 break‐out sessions and all problems were eventually resolved in 50% of cases. In the end, Applicants had to amend the SPC to

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comply with MSs’ requirements in 2 DCPs, withdraw from 1 of the 16 CMSs in 1 DCP; 2 other DCPs were taken to ‘automatic arbitration’.

Table 28 provides an overview of the outcome of the break‐out sessions.

4.7 DCPs Final outcome: withdrawal, approval and referral rates

Withdrawals Applicants withdrew from 6 (1.5%) CMS procedures (2 withdrawals occurred in a same DCP). In 2 DCPs, the proposed target species did not apply to the reference product as marketed in the CMS and the application was going to be rejected unless efficacy was demonstrated; the applicant decided to withdraw instead.

Approvals The approval rate was 100% for 20 of the CMSs in 2006‐07. The Netherlands, UK and France approved respectively 95%, 94% and 93% of the procedures. The CMSs with the lowest approval rate was Sweden (83%), followed by Ireland (87%) and Germany (89%).

Referrals (inclusion criteria: Day 60 CMD(v) referral fell in 2007) A total of 3 procedures were referred to CMD(v) by France, the Netherlands and Ireland, corresponding to 0.5% of the CMS procedures. Two were generic products, the other one a vaccine. The two pharmaceuticals were referred to CVMP, where they received a positive opinion. Note: a separate survey on CMD(v) and CVMP referrals is being carried out.

Figure 24: CMS outcome in DCPs in 2006‐07

Further detailed figures are given in Table 29 in Annex I.

4.8 Functioning of the Decentralised Procedures


RMSs rated the 33 procedures either ‘acceptable’ 12%, ‘good’ 42.5% or ‘excellent’ 33.5%. No procedure was rated ‘poor’ or ‘below par’; 12% of answers to this question were not available (see Table 30).

Functioning with the Applicants Major good points RMSs mostly reported on good communication with the applicant, promptness in providing requested information, competency and professionalism.

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Reported main difficulties The following 3 main difficulties were reported: ‐ The applicant decided to send an incomplete answer to LoQ I (data from an on‐going trial were missing). In the end, there was limited time for the RMS and CMSs to assess this trial, which was not very welcome. ‐ One question was inadequately addressed during the clock‐stop; this resulted in a follow‐up measure. ‐ One applicant chose not to have a meeting or discussion prior to responses to LoQ I, though this may have helped solving the major outstanding points.

Functioning with the CMSs

Major good points Overall, there was some positive feedback including: ‐ Good communication that allowed solving issues; ‐ Only a few issues carried over to step II of the DCP; ‐ CMSs sticking to the clock and being cooperative.

Reported main difficulties 35% of RMSs reported on the following difficulties with CMSs: ‐ High number of questions and data requirements related to national provisions; ‐ CMSs raising ambiguous comments, rather than compromising proposals; ‐ Non‐attendance at CMD(v) meetings (this caused delay in 1 procedure where major issue had to be discussed); ‐ Questions being sent quite late.


The APPs were generally satisfied with most aspects of the procedures, which were rated ‘acceptable’ 3%, ‘good’ 61%, or ‘excellent’ 21%. The remaining 15% did not answer the question and none of the DCPs was rated by applicant as ‘poor’ or ‘bellow par’ (see Table 30).

Functioning with the RMSs

Major good points A great number of applicants’ (95% of the 21 answers) acknowledged the very good communication with RMSs, their availability at any step of the procedure, openness for discussions of outstanding issues, provision of appropriate guidance and successful negotiation with reluctant CMSs.

Reported main difficulties The majority of applicants (61% of 21 respondents) did not encounter major difficulties with RMSs during the procedures, only the following were reported on individual procedures: ‐ Similar questions should be put together; ‐ Unavailability of the RMS assessor during completion of responses to LoQ I; ‐ Limited help in solving SPC issues.

Functioning with the CMSs Major good points According to applicants, the major good points with CMSs were good communication and acceptance of responses at step I that led to reduced number of step II questions. A few applicants also acknowledged that CMSs were cooperative and adhered to the timetables.

Reported main difficulties 38% of applicants that answered this question had no major problems with CMSs. The majority of problems encountered regarded some CMSs failing to grant MA within 30 days and some CMSs

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relying on national requirements, such as non‐acceptance of “essential‐similarity” with a reference product, request for translated SPC during validation phase.

4.9 General feedback to the DCP in comparison to the MRP

The general comment by RMSs was that DCP functioned very well for 70% of the procedures. The DCP further allows the RMS to raise questions till the end of the procedure. More than 30% of the RMSs claimed that the time to prepare LoQ I and assess applicants’ responses is too tight. Generic procedures went very well for those where the reference product SPC already was harmonised. Exchange of information on a reference product not authorised in the RMS was an issue.

Applicants who answered that question (n=27, 45%) found the procedure easier to handle compared to MRP, as most issues can be resolved during step I when the applicant has more time to analyse questions and provide responses. More than 30% of applicants believed the DCP to be faster than MRP, since the DCP allows skipping the National step preceding an MRP. One applicant still pointed that cooperation and communication with the RMS is more important in the DCP than in the MRP. One applicant did not perceive any significant difference between MRP and DCP and claimed that SPC harmonisation for generic products is quite a complicated process. The RMS option to leave out/merge CMSs questions is appreciated in order to keep LoQ I manageable both for the applicant and the assessor. However there is not enough time for RMS and CMSs to discuss LoQ I between day 100 and 105; this may result in the need to deal with additional CMSs queries during the clock stop period.

5. DISCUSSION

5.1 General discussion points

The use of the MRP and DCP The MRP is still widely used, though a decrease in the number of first and extension applications was noted in 2007 (n=88 vs n=95 in 2006); the number of repeat use MRPs has on the other hand more or less doubled in 2007 (n=19 vs n=10 in 2006). Furthermore, 33 DCPs were concluded since its introduction in November 2005 (n=3 in 2006 and n=30 in 2007), 57% of which were for generic products (vs. 26% of MRPs). In terms of products, when summing up first and extension MRPs and DCPs, a total of 27 vaccines and 75 pharmaceuticals (including 40 generic products) were granted marketing authorisations in 2007 across the EU; this represented a total of 102 products, which is the highest number of first applications ever reached (maximum first MRPs was 85 in 2006).

Involvement of the Member States The UK, Ireland and France remained the most used RMSs in both MRP and DCP in 2007. The number of CMS procedures in MRP slightly decreased, but together with the DCP, this figure has in fact increased considerably to reach a total of 1076 CMS procedures; involvement of Austria, Netherlands, Portugal, Spain and Sweden particularly increased. A limited number of repeat use procedures (n=5) were ran to expand the market of existing products to the MSs that joined the EU in 2007, i.e. Bulgaria and Romania.

Outcome The % of non‐validated CMS in MRPs increased in 2007, while all DCPs were validated. The % of withdrawals in MRP was exceptionally high in 2007 because of a withdrawal from all CMSs in 1 procedure. In the DCPs, there were withdrawals from 6 CMS procedures, though no serious risk issue was highlighted, i.e. no referrals occurred in any of these DCPs.

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All parties involved with MRPs and DCPs in 2007, i.e. CMD(v), EGGVP and IFAH‐Europe, further contributed individually to this survey discussion, as presented below.

5.2 CMD(v) discussion

Industry, Member States and CMD(v) should be congratulated for ensuring another successful year for processing Mutual Recognition and, in particular, the Decentralised Procedure. In the vast majority of cases, Mutual Recognition has continued to operate efficiently and to predictable timelines. 2007 is also the first year in which the majority of the early Decentralised Procedures have been finalised. However, not everything ran smoothly and there are areas which could be improved from both the CMD(v) and industry perspectives.

Looking at the positives, a major success for all is the operation of the Decentralised Procedure (DCP). This is a fast track route for applicants to gain an authorisation simultaneously in different Member States. The trade off is that the dossiers submitted must be of a high standard. All parties are taking an active part in assuring the realisation of this procedure. Member States are committed to making the procedure function and this is evident by the relatively low numbers of questions asked during the second phase of the procedure. Industry is submitting good quality dossiers – with a few procedures even finishing at day 120. These are early signs that the DCP is becoming the authorisation route of choice for products having not received a marketing authorisation at the time of application. This in itself brings good news and bad. The good news is that the procedure works – the co‐operation and involvement of the RMS and CMSs during the first assessment phase ensures that all the major issues can be aired and addressed during the clock stop period. The bad news is that the more popular this procedure becomes the greater the pressure on the RMS, particularly at the end of the first phase when the company responses have to be assessed in a very limited and demanding period. Over the coming year Reference Member States will need to plan carefully to ensure that resources are available to assess such applications.

Nevertheless, Mutual Recognition still accounts for the bulk of procedures. However, even with these there has been some success. The Mutual Recognition Procedure (MRP) has been in operation now for many years and it is easy to become complacent and take the procedure for granted. It is worth reflecting that MRP does work. The vast majority of procedures ran smoothly and ended up with products successfully authorised in the Concerned Member States. On many occasions procedures scheduled for discussion at CMD(v) were not discussed as all of the major issues were resolved beforehand.

Furthermore, only 8% of MRP or DCP ending in 2007 were referred to CMD(v) under the 60 day referral procedure. Of these CMD(v) resolved 40% and only 4 were sent onwards to a CVMP referral. Two others were referred to CMD(v) in December but at the time of writing the CMD(v) 60‐day referral procedure had not been concluded.

The 60 day referral process is still in its infancy but it is proving successful. As more and more precedents are set it is expected that the numbers of referrals resolved by CMD(v) will increase. In fact it is hoped that such precedents will prevent a CMD(v) referral in the first place.

There has also been a great deal of work undertaken by CMD(v) that, although not directly related to the management and facilitation of the procedures, has contributed, and will contribute, to more efficient running of MRP and DCP. For example, in response to the industry request to tackle the very real difficulties with diluents, CMD(v) set up an ad‐hoc working group to explore this issue and to put forward solutions. This group did exactly that – Member States have agreed to a compromise solution that all can accept whilst still respecting various national legislative requirements. It might not go as far as the industry ideal but it is an improvement, which will benefit applicants. The labelling ad‐hoc working group, again commissioned following discussion with industry, have made progress with agreeing some common positions between Member States. Whilst this is still early days it is hoped that these agreements can help to minimise the administrative burdens and costs associated with the

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labelling and packaging of products. There have been other improvements, for example, circulating the draft assessment report at day 70 of the DCP to the applicant in order to aid transparency and give the applicant advance warning of some of the issues they would have to address during the clock stop period; and the agreement to accept black and white texts (mock‐ups) in 3x English. Work has continued on refining, or developing, Best Practice Guides so that all parties have a shared understanding of what is required. CMD(v) also spends a significant amount of time discussing pre‐submission regulatory questions – this helps to avoid any unnecessary delays at validation or during the procedure itself.

Inevitably, things do go wrong and 2007 was no exception. Generics are an expanding area and one which has probably caused CMD(v) the most difficulty. The regulatory requirements have changed and throughout 2007 the Commission has clarified a number of issues. It is possible for applicants to use a European Reference Product and for Member States to accept the SPC of the Reference Product authorised in the RMS, which may include additional species, indications or even a different withdrawal period. The majority of the Member States accept these principles but the devil is in the detail and how this is practically applied causes difficulties, particularly as it is sometimes difficult to introduce a blanket agreement when products are so variable. Member States have the ultimate responsibility for authorising products within their territory and they must be satisfied that the products they are authorising are safe and efficacious. The challenge is in balancing this obligation against accepting products with additional species or indications etc, or even a European Reference Product, when Member States have no prior knowledge of the additions or the product itself. Furthermore, these applications are based on old reference products, authorised at a time when standards were different. We are all still getting used to the new regime for generics and it is fair to say that all parties have all experienced teething problems. Indeed, in some cases the RMS has had to respond to questions raised regarding the safety and efficacy of the authorised reference products. CMD(v) is working on a guidance document and The Heads of Medicines Agencies (Vet) have also been involved in these discussions. There is a desire from Member States to work together and CMD(v) is confident that the difficulties with processing generics will be overcome in time.

It is also true to say that attendance at CMD(v) meetings, to discuss major issues which have been raised, continues to be a problem. Whilst greater use of other media, such as video or telephone conferences, took place, there are still occasions where a CMS raises a major issue and then is not in a position to discuss this at the meeting. This is an irritation for all and something that Member States must improve during the coming year. This was also an issue raised in the 2006 survey report. It is worth noting that CMD(v) has committed itself to review the suggested areas for improvement highlighted by the industry in the 2006 report, during 2008. It should be stressed that the outcomes cannot be predicted at this time – CMD(v) will explore the issues and will put forward recommendations accordingly. These might range from a radical change to no change at all. Industry will be kept informed as the issues are discussed and hopefully there will be more to report in this section of the 2008 survey report.

Industry might want to also review some issues. Both regulators and industry have a role to play in helping to improve the facilitation of procedures. It is known that validation causes difficulties and each Member State may have their own national requirements. This is something IFAH‐Europe has discussed with CMD(v) during the interested parties meetings and these discussions will no doubt continue during 2008. However, a number of common validation failures do seem to occur for example non‐payment of fees. In the long run it would be helpful to applicants if greater attention could be paid to Chapter 7 of Volume 6A of the Notice to Applicants before submitting dossiers. It must be extremely frustrating to have submitted a dossier for it then not to pass validation and possibly miss the intended start date. The plea is, therefore, to submit the dossier in good time and give a little extra thought to the validation requirements in the various Member States.

CMD(v) has also expressed concerns on a few occasions that applicants might be circumventing Mutual Recognition, or at least the spirit of Mutual Recognition. Sometimes it is not entirely clear

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from the application form whether the applicant is involved in a concerted practice (as defined in Notice to Applicants) that would prevent a national only application being made.

Another area that is a continued difficulty is at the end of the procedure, in processing the national phase. There are times when the translations provided by the applicant are simply not good enough to enable the accepting Member State to issue the Marketing Authorisation. These translations need to be returned for further revision, which results in delays to issuing the Marketing Authorisation. Clearly, this is a source of frustration for all – the applicant wants to receive their marketing authorisation and Member States want to close the procedure.

It is also felt that if applicants followed the QRD template more closely then the numbers of SPC and product literature related questions may be reduced accordingly.

Finally, to end where we started, this has been a good and positive year. The systems work and procedures have been finalised following a predictable time‐line. Co‐operation between Member States continues to develop and this is reflected in the success of the Decentralised Procedure and in the numbers of Mutual Recognition Procedures not requiring discussion at CMD(v). Not least, Bulgaria and Romania have joined the EU and are taking part in procedures and also at CMD(v). However, involved parties must not rest on our laurels; there are improvements for us all to take. With Member States working together and with Member States working with industry these improvements can be become a reality.

5.3 EGGVP discussion

EGGVP wishes to thank CMD(v) and IFAH‐Europe for having ran this survey on the MRP and DCP procedures in 2007 and for giving EGGVP the opportunity to contribute to the discussion. In 2007, the implementation of the new legislation and more specifically the harmonisation of member states interpretation of it developed further. The procedures ran rather smoothly and some aspects have even improved over the year as more harmonised views are obtained. Some of the major points for EGGVP cover the following:

The European reference product The non acceptance of this principle by a fair number of member states has caused several non validation and referral issues in 2007. As all member states have now agreed on this principle, the number of non validations and referrals should drop considerably and EGGVP wishes to thank member states for reaching this harmonised view. Even though the introduction of the European reference product was necessary to make generic application under the (obligatory) MRP or DCP possible, we do understand member states hesitations and can only hope that these will diminish over time by the increase of mutual trust in each other’s decisions.

Environmental Risk Assessment The requirement of the environmental risk assessment for generic applications has negatively influenced the number of applications and has also had an impact on the number of safety questions. More clarity on the requirements, especially for generics in relation to the potential risks, might reduce this effect in the future.

Number of questions The number of questions in MRP, whether minor, major or product literature related, remains an area of concern as it reflects the different views of member states. As last year, several MSs do not ask any questions and they run already a true 'mutual recognition' procedure rather than a complete re‐assessment. We hope this group will grow in the coming years. A mandate for CMD(v) to decide by majority whether or not questions are related to a potential serious risk and to dismiss questions that are not, would greatly improve the number of questions and the effectiveness of the referral period in both procedures.

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Participation of member states at break‐out sessions The attendance of member states with major questions at the break‐out sessions seems to be declining. It is now stated as 71% for MRP which means that almost a quarter is not present. In DCP this number is even higher as almost half is not present. For the success of these procedures the participation of all MS´s with major objections is essential. And with the current possibilities for videoconferencing, in our view, it should be possible to reach this objective.

Decentralised Procedure The introduction of this procedure has improved the process as it eliminates the national step and extends the time to answer the CMS questions.

National Requirements Many steps are already taken to eliminate national translations and mock‐ups at the start of or during the procedure. However, the survey shows that there is still room for improvement and we hope that the 2008 procedures can be run in English only. With regard to mock‐ups, the procedure would benefit from deleting these from the procedure and only require those prior to marketing on a national level.

In general, the MRP procedures and now hopefully also the DCP procedures are improving each year. We hope (and trust) we can continue this improvement as a joint effort of member states, practitioners and industry in 2008.

5.4 IFAH-Europe discussion

Use of the procedures The DCP is expected to become a popular choice of registration route for the animal health industry; it was also chosen over the Centralised Procedure in 2 cases as a way to limit the number of CMSs; it is therefore important that the choice of route of registration procedure is kept.

Number of Questions The average number of questions in MRP (n=76) remained fairly high, especially when compared to the number of questions at Step I of the DCP (n=72), i.e. procedures where no national assessment has previously been carried out and where more questions could be expected.

Break‐out sessions and referrals In MRP, 59% of the procedures had a break‐out session (increase in 2007 – see 39% in 2006) with focus on the SPC (discussed in 49% of all), whereas only 42% of the DCPs required a session to help resolving issues (SPC discussed in only 14%). This certainly remains a useful step of both procedures where issues can be solved; it is therefore important all CMSs raising objections do attend. The number of CMD(v) referrals in MRPs (including repeat use) decreased from 4.5% to 1.3% of all CMS procedures. The rate was of 0.5% in the DCPs. The IFAH‐Europe/CMD(v) independent survey on referral will allow to conclude on whether this decrease is to become a trend.

Overall view When looking at the following aspects of the procedures: ‘validation’, ‘number of questions’ and ‘outcome’, the DCPs appear to have run much more smoothly in comparison to MRPs in 2007. The DCP was indeed very welcomed by those applicants who used it for the first time. One challenging aspect remains to be addressed for industry, that is the reduction of the time to market by getting MSs to issue licences within 30 days of final translations being approved, as recommended in the CMD(v) Best Practice Guide.

Looking ahead to the future

With regard to the validation step, IFAH‐Europe advocates for all additional national requirements to be removed, particularly where they impede validation of an application (i.e. develop a unique application form across MSs, which will also permit a single electronic application form). In an enlarged EU of 27 MSs, this is becoming even more important as procedures have a much higher

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average of CMSs (n=12 in the DCPs). IFAH‐Europe acknowledges the CMD(v) commitment to set‐up a sub‐group with IFAH‐Europe to look at this aspect.

Furthermore, the European Reference Product concept clearly discriminates against pioneer companies who did not obtain a ‘full’ SPC in all MSs. To ensure a level playing field across the industry, IFAH‐Europe proposes to introduce an optional administrative procedure for simultaneous harmonisation of the SPC when used as European reference product. This aspect should be addressed in the framework of the ‘Variations review’.

6. CONCLUSION

This 2007 survey was the first to report on the functioning of both the Mutual Recognition and Decentralised Procedures, since the introduction of the latter in November 2005. This led to an increase in the number of applications, especially for generic products. In addition to this, seven CMD(v) referral reached Day 60 in 2007. Thus, it has been an extremely busy year for all parties, whose time taken to complete these survey questionnaires is greatly acknowledged by all.

Once again, this survey report will serve as a useful basis to strengthen relationship between CMD(v) and industry and especially address particular aspects of the MRP and DCP.

The IFAH‐Europe secretariat would like to express special thanks to the CMD(v) survey sub‐group for ensuring that accurate figures are provided in this report and for its valuable input in the finalisation of the document.

IFAH-Europe contact: Sylvie Meillerais, Technical Project Manager Tel: +32 (0)2 543 75 63 E-mail address: [email protected]

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mailto:[email protected]


ANNEX I: Tables

Table 1: Distribution of the 68 first MRPs by dossier type in 2007

Standard dossiers (n=32) Non-standard dossiers (n=36)

NAS Normal Art. 12

Generic Art. 13

WEU Art. 13a

Fixed Comb. Art. 13b

Inf. Cons. Art. 13c

IVMP Art. 13d

Total

Pharmaceuticals 0 13 23 7 3 2 0 48

Vaccines 0 19 0 0 0 0 1 20

Total 0 32 23 7 3 2 1 68

Table 2: Distribution of the 68 first MRPs by product type and target animals in 2007

Livestock Companion Both Total

Pharmaceuticals 27 20 1 48

Vaccines 12 7 1 20

Total 39 27 2 68

* for use in both livestock and companion animals

Return to 3.1 Application and product profiles

Table 3: RMSs in first and extension MRPs since 2003

AT CZ DE DK ES FI FR HU IE IT NL PT SE SK UK Total MRPs

Total RMSs

2003 0 NA 3 2 3 2 19 NA 13 7 10 0 0 NA 23 82 9

2004 0 0 10 1 2 1 4 0 7 2 1 0 0 0 15 43 9

2005 0 0 8 0 2 0 14 0 25 0 2 0 3 1 14 69 8

2006 0 3 6 1 6 1 14 3 22 0 8 0 0 2 19 85 11

2007 1 0 8 0 6 1 7 2 10 2 0 1 3 1 27 69 12

Return to 3.2.1 Involvement as RMS

Table 4: RMSs in Repeat Use MRPs since 2003

CZ DE DK FI FR IE NL SE UK Total Repeat Use

Total RMSs

2003 NA 2 0 0 3 3 0 1 3 12 5

2004 0 2 0 0 1 2 0 0 7 12 4

2005 0 3 2 1 13 3 0 0 4 26 6

2006 0 3 0 0 3 2 0 1 1 10 5

2007 1 3 0 1 3 6 1 2 2 19 8

Go to 3.2.2 Involvement as CMS

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Table 5: CMSs in first and extension MRPs in 2007

AT BE BU CY CZ DE DK EE EL ES FI FR HU IE IT TOTAL

CMS proc. 35 35 9 18 28 34 24 11 31 49 19 36 27 32 37

LT LU LV MT NL PL PT RO SE SI SK UK IS LI NO

CMS proc. 12 23 12 4 37 27 45 10 24 18 26 19 0 1 20

703

Table 6: Average number of CMSs in full and generic dossiers since 2003

2003 2004 2005 2006 2007

Full dossier 11 (n=46) 12 (n=28) 12 (n=31) 10 (n=41) 13 (n=32)

Generic 8 (n=12) 9 (n=8) 6 (n=22) 8 (n=25) 8 (n=23)

Return to 3.2.2 Involvement as CMS

Table 7: CMSs in repeat use MRPs in 2007


CMS proc. 2 4 5 3 10 2 3 5 3 2 1 1 9 1 1


CMS proc. 6 1 4 1 3 11 3 5 4 3 8 3 0 0 3

107

Go to 3.2.2 Reasons for choice/exclusion of CMSs

Table 8: Quality of Applicants' dossiers and of RMSs’ Assessment Reports in first and extension MRPs since 2005

Quality of APP dossiers Quality of RMS AR

2005 2006 2007 2005 2006 2007

Poor 0% 0% 0% 0% 1% 0%

Below par 0% 5% 1.5% 0% 0% 0%

Acceptable 30% 22% 33% 7% 1% 10%

Good 54% 69% 57% 55% 71% 53.5%

Excellent 16% 4% 7% 36% 15% 27.5%

No answer 0% 0% 1.5% 2% 12% 9%

Return to 3.3.1

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Table 9: Range of questions asked in first and extension MRPs since 2003

Number of questions 0 - 50 51 - 100 101 - 150 151 - 200 > 200

Number of 2004 procedures (n=35) 11 (31%) 6 (17%) 12 (34%) 3 (9%) 3 (9%)

Number of 2005 procedures (n=69) 29 (42%) 25 (36%) 8 (12%) 4 (6%) 3 (4%)

Number of 2006 procedures (n=85) 36 (42.5%) 27 (32%) 13 (15%) 7 (8%) 2 (2.5%)

Number of 2007 procedures (n=68) 31 (45.5%) 17 (25%) 14 (20.5%) 3 (4.5%) 3 (4.5%)

Return to 3.5.1 Number of questions per dossier

Table 10: Number of questions by category in first and extension MRPs since 2005

2005 2006 2007

Mean Min-Max Mean Min-Max Mean Min-Max

Minor 14 0 - 52 16 0 - 58 12 0 - 52

Major 24 0 - 128 22 0 - 115 20 0 - 160

SPC 33 0 - 127 33 0 - 158 39 0 - 139

Table 11: Number of major questions by dossier parts in first and extension MRPs since 2005

2005 2006 2007

Mean Min – Max Mean Min – Max Mean Min – Max

Part I 0.3 0 - 5 0.3 0 - 4 0.1 0 – 9

Part II 10 0 - 63 9 0 - 72 9 0 – 83

IIIA 1 0 - 6 2 0 - 22 1.5 0 – 10 Pharm.

IIIB 1 0 - 9 1 0 - 7 1 0 – 12

Vac. Part III 11 0 - 38 10 0 - 25 6 0 – 18

Part IV 9 0 - 51 8 0 - 32 7 0 - 57

Return to 3.5.2 Questions by Category and Dossier part

Table 12: Average questions to a dossier per CMS in first and extension MRPs in 2007

AT BE BU CY CZ DE DK EE EL ES FI FR HU IE IT

Minimum 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0

Maximum 4 18 4 0 19 37 27 0 4 24 31 76 14 41 28

Average 0.5 2 1 0 5 19 10 0 0.3 6 12 30 4 18 7


Minimum 0 0 0 0 0 0 0 0 0 0 0 0 NA Not avail. 0

Maximum 0 0 0 0 15 33 13 0 42 2 4 51 NA Not avail. 12

Average 0 0 0 0 4 10 4 0 12 0.1 0.3 23 NA Not avail. 3

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Table 13: Average questions per CMS in relation to certain types of MRP dossiers since 2003

2003 2004 2005 2006 2007

Normal 11 (n=43) 8 (n=21) 8 (n=31) 9 (n=41) 6 (n=31)

WEU 16 (n=13) 11 (n=1) 10 (n=9) 9 (n=7) 10 (n=7)

Generic 8.5 (n=9) 13 (n=8) 8 (n=22) 7 (n=25) 8 (n=23)

Return to 3.5.3 Questions per CMS

Table 14: Average questions per category and CMS in first and extension MRPs in 2007


Parts I-IV 0.2 1 0.4 0 2 10 3.5 0 0.2 1.5 5 21 2 7 3

SPC, Lab., and PL 0.2 1 0.3 0 3 10 7 0 0.1 4.5 7 9 2 12 4.5


Parts I-IV 0 0 0 0 1.5 3 1 0 2.5 0.1 0.1 13.5 NA Not avail. 1

SPC, Lab. and PL 0 0 0 0 3 7 4 0 10 0.1 0.2 11 NA Not avail. 2.5

Return to 3.5.3 Questions per CMS

Table 15: Performance of the CMD(v) break‐out session in first and extension MRPs since 2003

2007 (n=41/69) 2003

(n=64/76) 2004

(n=26/35) 2005

(n=47/69) 2006

(n=33/85) n %

Procedures where CMSs who raised major objections attended 83% 86% 81% 89% 29 71%

Procedures where APP was immediately informed of the outcome 94% 84% 77% 45% 35 85%

Procedures where all problems were solved 23% 35% 31% 15% 25 61%

Procedures where APP made concessions to the SPC Not avail. Not avail. Not avail. 27% 7 17%

Procedures where applicants withdrew in one or more CMS 54% 43% 42% 28% 1* 2%

Procedures with break-out session taken to ‘automatic arbitration’ NA NA NA 33%b 4 10%

* In 2007, an applicant withdrew from all 23 CMSs in 1 procedure.

Return to 3.6 CMD(v) break-out sessions

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Table 16: Outcome per CMS in first and extension MRPs in 2007

AT BE BU CY CZ DE DK EE EL ES FI FR HU IE IT LT

Total as CMS 35 35 9 18 28 34 24 11 31 49 19 36 27 32 37 12

n not validated 0 0 0 0 0 2 1 0 1 2 1 1 0 0 1 0

n approved 34 34 8 17 28 30 22 10 29 46 17 31 26 31 34 11

% approved 97 97 89 94 100 88 92 91 94 94 89 86 96 97 92 92

n referred 0 0 0 0 0 2 0 0 0 0 0 3 0 0 1 0

% referred 0 0 0 0 0 6 0 0 0 0 0 8 0 0 3 0

LU LV MT NL PL PT RO SE SI SK UK IS LI NO Total

Total as CMS 23 12 4 37 27 45 10 24 18 26 19 0 1 20 703 1

n not validated 0 0 0 0 1 1 0 2 0 0 1 0 0 2 16

n approved 22 11 4 36 26 43 9 19 17 26 16 NA 1 17 655

% approved 96 92 100 97 96 96 90 79 94 100 84 NA 100 85 93.5%

n referred 0 0 0 0 0 0 0 2 0 0 1 NA 0 0 9

% referred 0 0 0 0 0 0 0 8 0 0 5 NA 0 0 1.5%

1 including 23 withdrawn in 1 MRP (3%)

Return to 3.7 Outcome

Table 17: Overall functioning of MRPs since 2005

RMS views APP views

2005 2006 2007 2005 2006 2007

Poor 0% 1% 2% 4% 1% 0%

Below par 0% 2% 2% 0% 2% 0%

Acceptable 26% 25.5% 20.5% 7% 8.5% 11.5%

Good 60% 65.5% 60% 49% 49.5% 53.5%

Excellent 14% 5% 13% 35% 24% 25%

No answer 0% 1% 2.5% 4% 15% 9%

Return to text

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Table 18: Distribution of the 33 DCPs by dossier type in 2006‐07

Standard Procedures Non-standard Procedures

NAS Normal WEU Generic Line Extension

Not known

Total

Pharmaceuticals 0 4 1 17 1 1 24

Vaccines 0 9 0 0 0 0 9

Total 0 13 1 17 1 1 33

Table 19: Distribution of the 33 DCPs by product and target animal in 2006‐07

Livestock Companion Both * Total

Pharmaceuticals 10 13 1 24

Vaccines 3 6 0 9

Total 13 19 1 33

* for use in both livestock and companion animals

Go to 4.2 Involvement of the MSs in DCPs

Table 20: Involvement as RMS in DCPs in 2006 and 2007

DE DK ES FR IE NL UK Total DCPs

Total RMSs

2006 0 0 0 0 0 0 3 3 1

2007 2 1 1 8 7 2 9 30 7

Table 21: Involvement as CMS in DCPs in 2006‐07


CMS proc. 24 22 0 11 19 19 14 3 23 28 13 15 18 15 26


CMS proc. 10 15 6 3 20 18 22 0 12 9 15 18 0 0 9

407

Go to 4.3 Validation

Table 22: Rating of documents by RMSs and Applicants in DCPs in 2006‐07

Step I Step II

APP dossier Draft AR

APP response to LoQ II

RMS AR of response to LoQ II

Rating by RMSs Applicants RMSs Applicants

Poor 0% 0% 0% 0%

Below par 0% 0% 0% 0%

Acceptable 12% 3% 12% 0%

Good 70% 85% 67% 88%

Excellent 0% 3% 3% 0%

No answer 18% 9% 18% 12%

AR = Assessment Report Go to 4.4.2 LoQ I or to 4.5 Assessment Step II

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Table 23: LoQ I by category (mean, min. and max.) in DCPs

2006-07

Mean Min - Max

Parts I to IV 51 20 - 116

SPC 24 0 - 79

Table 24: LoQ I by dossier part in DCPs

2006-07

Mean Min – Max

Part I 4 1 - 25

Part II 32 13 - 73

IIIA 3 0 -10 Pharm.

IIIB 1.5 0 - 16

Vac. Part III 7 0 - 23

Part IV 10 1 - 52

Return to 4.4.2 LoQ I Table 25: LoQ II by category (mean, min. and max.) in DCPs

2006-07

Mean Min - Max

Points for clarification 2 0 - 11

Parts II to IV 7 0 - 36

SPC 15 0 - 40

Table 26: LoQ II by dossier part in DCPs

2006-07

Mean Min – Max

Part II 4 0 - 23

IIIA 0.1 0 - 1 Pharm.

IIIB 1 0 - 6

Vac. Part III 3 0 - 5

Part IV 2 0 - 10

Return to 4.5.2 LoQ II

Table 27: Average LoQ II to a dossier per CMS in DCPs in 2006‐07


Minimum 0 0 NA 0 0 0 0 0 0 0 0 0 0 0 0

Maximum 0 2 NA 0 8 13 11 0 1 37 15 20 5 21 12

Average 0 0.5 NA 0 1 6 3 0 0.1 6 4 7 0 4 2


Minimum 0 0 0 0 0 0 0 NA 0 0 0 0 NA NA 0

Maximum 0 0 0 0 0 6 6 NA 10 0 5 22 NA NA 12

Average 0 0 0 0 2 1 1 NA 3 0 0.5 4 NA NA 0.1

Return to 4.5.2 LoQ II


Table 28: Performance of the CMD(v) break‐out session in DCPs in 2006‐07

2007 (n=14/29) * n %

Procedures where all CMSs who raised major objections attended 8 / 14 57%

Procedures where APP was immediately informed of the outcome 12 / 14 86%

Procedures where all problems were solved at break-out session 7 / 14 50%

Procedures where APP made concessions to the SPC 2 / 14 14%

Procedures where applicants withdrew from one or more CMS 1 /14 7%

Procedures taken to ‘automatic arbitration’ 2 / 14 14%

* Information only available where questionnaire have been completed

Go to 4.6 CMD(v) breakout session for DCPs

Table 29: Approval rate per CMS in DCPs in 2006‐07

AT BE BU CY CZ DE DK EE EL ES FI FR HU IE IT LT

Total as CMS 24 22 0 11 19 19 14 3 23 28 13 15 18 15 26 10

n withdrawn 0 0 NA 0 0 2 0 0 0 0 0 0 0 1 0 0

% withdrawn 0 0 NA 0 0 10 0 0 0 0 0 0 0 7 0 0

n approved 24 22 NA 11 19 17 14 3 23 28 13 14 18 13 26 10

% approved 100 100 NA 100 100 89 100 100 100 100 100 93 100 87 100 100

n referred 0 0 NA 0 0 0 0 0 0 0 0 1 0 1 0 0

% referred 0 0 NA 0 0 0 0 0 0 0 0 7 0 7 0 0

LU LV MT NL PL PT RO SE SI SK UK IS LI NO Total

Total as CMS 15 6 3 20 18 22 0 12 9 15 18 0 0 9 407

n withdrawn 0 0 0 0 0 0 0 2 0 0 1 NA NA 0 6

% withdrawn 0 0 0 0 0 0 0 17 0 0 6 NA NA 0 1.5%

n approved 15 6 3 19 18 22 NA 10 9 15 17 NA NA 9 398

% approved 100 100 100 95 100 100 NA 83 100 100 94 NA NA 100 98%

n referred 0 0 0 1 0 0 NA 0 0 0 0 NA NA 0 3

% referred 0 0 0 5 0 0 NA 0 0 0 0 NA NA 0 0.5%

Go to 4.7 DCPs Final outcome: approval and referrals rates

Table 30: Overall functioning of DCPs in 2007

RMS APP

Poor 0 0

Below par 0 0

Acceptable 12% 3%

Good 42.5% 61%

Excellent 33.5% 21%

No answer 12% 15%

Return to 4.8 Functioning of the procedure

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ANNEX II: List of acronyms

APP Applicant

CMD(v) Co-ordination Group for Mutual Recognition and Decentralised Procedures - Veterinary (ex-VMRFG) http://www.hma.eu/cmdv.html

CMS(s) Concerned Member State(s)

CP Centralised Procedure

CVMP Committee for Medicinal Products for Veterinary Use

DCP Decentralised Procedure

EGGVP European Group for Generic Veterinary Products - http://www.eggvp.org/

EEA European Economic Area (EU plus Norway, Iceland and Liechtenstein)

EMEA European Medicines Agency - http://www.emea.eu.int/

ERA Environmental Risk Assessment

GL Guideline

HEVRA/HMA Heads of European Veterinary Regulatory Authorities / Heads of Medicines Agencies - http://www.hma.eu

IFAH-Europe International Federation for Animal Health - Europe (since January 2003 - previously known as FEDESA) http://www.ifahsec.org/Europe

IVMP Immunological Veterinary Medicinal Product

LoQ List of Questions

MA Marketing Authorisation

MAH Marketing Authorisation Holder

MRLs Maximum Residue Limits

MRP(s) Mutual Recognition Procedure(s)

MS(s) Member State(s)

MSs codes AT Austria BE Belgium BU Bulgaria CY Cyprus CZ Czech Republic DE Germany DK Denmark EE Estonia EL Greece ES Spain FI Finland FR France HU Hungary IE Ireland IT Italy LT Lithuania LU Luxemburg LV Latvia MT Malta NL Netherlands PL Poland PT Portugal RO Romanaia SE Sweden SI Slovenia SK Slovakia UK United Kingdom LI Liechtenstein IS Iceland NO Norway

NAS New Active Substance

NtA Notice to Applicants http://pharmacos.eudra.org/F2/eudralex/vol-6/home.htm

PL Package Leaflet

PLit Product Literature

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http://www.hma.eu/cmdv.html

http://www.eggvp.org/

http://www.emea.eu.int/

http://www.hma.eu/

http://www.ifahsec.org/Europe

http://pharmacos.eudra.org/F2/eudralex/vol-6/home.htm


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RMS(s) Reference Member State(s)

SPC Summary of Products Characteristics

SOP Standard Operating Procedure

TGD Technical Guidance Document

VMRFG Veterinary Mutual Recognition Facilitation Group (now CMD(v))

VMP Veterinary Medicinal Product

WEU Well Established Use

WP Withdrawal Period

cmd(v)/ifah-europe 2007 survey on the …product profile: of the 69 first and extension procedures,...

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