ifah-europe / vmrfg 2002 survey on the mutual …€¦ · the product profile: of the 87...

IFAH-Europe / VMRFG 2002

SURVEY ON THE

MUTUAL RECOGNITION

PROCEDURE FOR

VETERINARY MEDICINAL

PRODUCTS

JUNE 2003

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TABLE OF CONTENTS

TABLE OF CONTENTS................................................................... 1

EXECUTIVE SUMMARY................................................................. 2

SUMMARY STATISTICS................................................................ 3

1. BACKGROUND ......................................................................... 5

2. METHOD ................................................................................. 5

3. RESULTS AND COMMENTARY ................................................... 6

1. RESPONSE TO THE QUESTIONNAIRE. ............................................... 6 2. APPLICATIONS AND PRODUCT PROFILES........................................... 6 3. INVOLVEMENT OF THE MEMBER STATES. .......................................... 7 4. NATIONAL ASSESSMENT PROCEDURES BY THE RMSS............................ 9 5. VALIDATION .......................................................................... 10 6. NUMBER OF QUESTIONS PER CMS. ............................................... 11 7. NUMBER OF QUESTIONS PER PROCEDURE AND PER DOSSIER PART. ......... 12 8. VMRFG DISCUSSION............................................................... 13 9. WITHDRAWALS FROM THE CMSS AND ARBITRATION. ........................ 14 10. POST DAY 90: SENDING TRANSLATIONS AND ISSUING LICENCES......... 16 11. FUNCTIONING OF THE PROCEDURES AND MAJOR PROBLEMS REPORTED. . 18 12. PROPOSALS FOR IMPROVEMENT. ................................................ 19

4. DISCUSSION......................................................................... 20

5. CONCLUSION ........................................................................ 22

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VMRFG/IFAH-Europe 2002 SURVEY OF

THE MUTUAL RECOGNITION PROCEDURE

EXECUTIVE SUMMARY

§ Sample profile : there were 87 mutual recognition procedures (MRP) in 2002 initiated by 26 different companies; 3 of them were first time users.

The product profile : of the 87 procedures, 70 (80%) were for pharmaceuticals and 17 (20%) for vaccines. As in previous years, the number of applications for vaccines was much lower than for pharmaceuticals. Of these 87 procedures, 2 are for products for use in both companion and food-producing animals, which gives a total of 50 (56%) products for livestock and 39 (44%) for companion animals; this distribution is more even than in 2001 (33/6 ratio).

The applications profile : there were 5 line extensions; the 57 first procedures were distributed as follows: 31 normal procedures (including 2 new indications), 13 generic, 7 informed consent (6 for the same product at various strengths and for use in cats and dogs), 5 bibliographic and 1 fixed combination. There were 25 repeat use procedures (cf. 3 in 2001), including 2 bibliographic and 2 generic.

§ RMS and CMS: 10 member states acted as Reference Member State (RMS), including Belgium and Spain for the first time since 1998. The main reason for choice of RMS was a positive previous experience with the national agency. All 15 EU member states, plus Iceland (n=1) and Norway (n=20) were chosen as Concerned Member States (CMSs), mostly for marketing reasons. The Czech Republic and Hungary were also involved as CMS in some MR procedures.

§ Questions (data based on 77 procedures, including 20 repeat use): the CMSs asked an average of 8 questions per procedure (c.f. 9 and 7 in respectively 2000 and 2001); and each dossier received an average of 49 questions (c.f. 80 and 40 in respectively 2000 and 2001). For first procedures, most questions focused on the SPC with 46%, similar to 2001 (cf. 39% in 2000). Most major questions were on Parts II (36%) and IV (42%) of the dossier (cf. 36% and 39% in 2001).

§ Post day 90 (data based on 57 first and line extension procedures): the average time taken by applicants to supply final translations remained consistent compared to 2001, with 32 days (cf. 19 in 2000 and 33 in 2001), as did the average time taken to obtain a national licence from receipt of the final translations with 57 days (cf. 48 in 2000 and 57 in 2001).

§ Level of satisfaction (data based on all 87 procedures): overall, applicants and RMSs were very pleased with each party’s performance. Most difficulties occurred between applicants and CMSs, especially one first time user, and led to 2% rejections at validation and 10% withdrawals (cf. respectively 2% and 12% in 2000 and 4% and 7% in 2001).

§ Arbitration: unsolved issues led to 5 veterinary arbitration procedures (i.e. 2 products + 3 strengths of a third one) (cf. 1 in 2001). The CVMP delivered a favourable opinion to market the products in all cases and a positive Commission decision followed for all of these applications.

§ View of the VMRF Group on the outcome of the survey: the VMRFG group dealt with an increased number of applications in 2002 and the procedures worked generally well. The increased percentage of withdrawals and arbitrations should be taken in the context of the reduced percentage of rejections at validation; the latter may reflect an improvement in the quality of dossiers submitted. Some differences of interpretation between MSs remain, and the VMRFG is taking actions to address these.

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SUMMARY STATISTICS - 2002

§ INVOLVEMENT OF THE MEMBER STATES:

Survey Period: 1995–98 1 1999 1 2000 2 2001 2 2002 2 Overall

Number of countries as RMS: 5 5 7 8 10 10

Number of countries as CMS: 15 15 17 17 17 17

Number of Mutual Recognition Procedures: 20 22 47 40 87 216

Total number of CMS procedures: 149 170 403 * 235 * 526 * 1483

Average number of CMSs per procedure: 8 8 9 6 6 7

1: survey sample * including rejections at validation (see table below) 2: all procedures (including Norway and Iceland, involved for the 3rd time in 2002 in respectively 20 and 1 procedure)

§ OUTCOME OF THE PROCEDURES:

Survey Period: 1995–98 1 1999 1 2000 2 2001 2 2002 2 Overall

Total number of CMS procedures: 149 170 403 231 526 1483

Total number rejected at validation: -- -- 7 10 8 25

% Total rejection at validation: -- -- 2% 4% 2% 3%

Total number withdrawn: 16 13 48 16 52 145

% Total withdrawn: 11% 8% 12% 7% 10% 10%

Procedures taken to arbitration: 0 0 0 1/40 5/87 6

% Arbitration: 0% 0% 0% 2.5% 6% 3%

1: survey sample 2: all procedures (including Norway and Iceland involved for the 3rd time in 2002 in respectively 20 and 1 procedure)

§ NUMBER OF QUESTIONS (n = survey sample size):

Survey Period: 1995–98 (n=20)

1999 (n=22)

2000 (n=35)

2001 (n=39)

2002 (n=77*)

Overall average (and max.) number of questions per procedure:

55 (193) 68 (254) 80 (212) 40 (165) 49 (256)

Overall average (and max.) number of questions per procedure and per CMS:

8 (72) 9 (73) 9 (56) 7 (43) 8 (59)

* 77 = 57 first procedures and line extensions + 20 repeat use procedures

§ DAYS FOR ACCEPTED TRANSLATIONS TO BE SENT AND LICENCES TO BE ISSUED:

Survey Period: 1995–98 (n=20)

1999 (n=22)

2000 (n=35)

2001 (n=39)

2002 (n=57*)

Average (and max.) number of days from Day 90 to send translations: N.A. 15 (99) 19 (133) 33 (235) 32 (216)

Average (and max.) number of days from translations to licences: 1 N.A. 55 (180) 48 (339) 57 (315) 57 (276)

Average (and max.) number of days from Day 90 to issue of a licence: 71 (312) 70 (180) 67 (339) 90 (349) 89 (401)

1: calculated from day 90 if translations were accepted before or at day 90 (n=13 in 2001, n=42 in 2002), or from the Commission’s decision day if the procedure went to arbitration (n=1 in 2001) * repeat use procedures excluded due to insufficient data

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§ THE PRODUCTS PROFILE SINCE 1999:

10

2833

50

1219

6

39

0

10

20

30

40

50

60

1999 (n=22) 2000 (n=47) 2001 (n=39) 2002 (n=87)

Livestock

Companion

(n = number of procedures)

§ THE APPLICATIONS PROFILE SINCE 2000:

2000 2001 2002

1st procedures 41 37 62

Repeat use 6 (13%) 3 (7.5%) 25 (29%)

Total 47 40 87

§ APPLICATIONS AND PRODUCT PROFILE IN 2002:

1st procedures

New Active Ingredient

1st procedure Others *

Line Extension Repeat use

Pharmaceuticals 0 43 5 22

Vaccines - 14 0 3

Total 0 57 5 25

* Normal / Informed consent / Bibliographic / Generic / Fixed combination

17

30 30

70

5

179

17

0

10

20

30

40

50

60

70

80

1999 (n=22) 2000 (n=47) 2001 (n=39) 2002 (n=87)

Pharmaceuticals

Vaccines

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MUTUAL RECOGNITION PROCEDURE

VETERINARY MEDICINAL PRODUCTS 2002

1. BACKGROUND

§ Reasons for a survey: In 1998, the mutual recognition procedure became compulsory for companies wishing to register a product in more than one member state. The functioning of this procedure has continued to improve year on year thanks to the creation of, and initiatives of the Veterinary Mutual Recognition Facilitation Group (VMRFG) in dialogue with FEDESA, now IFAH-Europe since January 2003. The annual survey of the functioning of the procedure is seen as a valuable tool for monitoring the functioning of the procedure, identifying areas where improvement is needed and assessing progress; it also aims to facilitate the dialogue between the VMRFG and industry.

§ Joint collaboration between IFAH-Europe and VMRFG: The first survey was initiated by FEDESA in 1999 (covering procedures from 1995 to 1998). All subsequent surveys became a joint collaboration between FEDESA and the VMRFG. The questionnaire and report have evolved to re-focus on specific areas of interest (e.g. major and SPC questions, withdrawals and arbitration), while maintaining the ability to follow the main trends. The close collaboration between the VMRFG and IFAH-Europe has allowed a significant number of completed questionnaires to be returned in due time to enter this survey.

2. METHOD § Data collection procedure: The criteria for inclusion of a procedure was that day 90 of the MRP fell in the year 2002 (see: VMRF/032/02 “Procedure for collection of data and handling replies to VMRFG/FEDESA MRP Questionnaire” adopted in May 2002). The revised questionnaire VMRF/030/02, which came into effect in May 2002, was used for this survey. After day 90, the RMS completed its section of the questionnaire and sent it to the applicant. The applicant completed its section and then returned a copy of the questionnaire to the RMS. A copy was also sent to IFAH-Europe. Thus both the RMS and the applicant were able to obtain immediate feedback on the views of the other party on the functioning of that procedure. IFAH-Europe received a total of 55 questionnaires, covering 90% (78/87) of the MR procedures. VMRFG provided basic data on the remaining 9 procedures.

§ Data analysis and reporting: The data from the completed questionnaires were tabulated and summarised by the IFAH-Europe technical coordinator, and checked by 6 volunteers of the VMRFG. The information was treated confidentially and data were ‘cleaned’ to maintain anonymity. Due to the high number of repeat use procedures (n=25), these were analysed and are reported separately from the first and line extension procedures (n=62).

The draft report was prepared by the IFAH-Europe technical coordinator and sent for consultation to the VMRFG and the IFAH-Europe Regulatory Procedures ad hoc group. The final report was then sent to all participants and made available on the IFAH-Europe and HEVRA websites.

It is anticipated that the key issues and conclusions of the survey will be reported at an EMEA/VMRFG/IFAH-Europe info day in the second half of 2003 from the perspective of both industry and VMRFG.

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3. RESULTS AND COMMENTARY

1. Response to the questionnaire. The 55 completed questionnaires were received from 26 different companies, covering 78 procedures fulfilling the inclusion criterion of day 90 falling in 2002. Of these 78 procedures, 58 are first and line extension procedures and 20 are repeat use procedures.

The VMRFG provided the data on “Applications and products’ profile” (section 2), “Involvements of the member states” (section 3) and “success rates” (section 9) for all 87 procedures (62 first and line extension procedures and 25 repeat use procedures).

As in previous years, the questionnaires were generally well completed by both RMSs and applicants, apart from the data on: “dates translations sent” and “dates licences issued” (by the applicant), however not always available at the time of closure of the data entry.

The number of procedures that each section of the report is based on is indicated at the beginning of each paragraph; the table below describes the data source for each (n) number:

(n) Data source

87 All procedures (additional data provided by VMRFG)

62 All 57 first procedures and 5 line extension (additional data provided by VMRFG)

25 All repeat use procedures (additional data provided by VMRFG)

58 53 first procedures and 5 line extension for which a questionnaire was received, including 1 procedure rejected at validation

57 52 first procedures and 5 line extension for which a questionnaire was received, excluding 1 procedure rejected at validation

20 Repeat use procedures for which a questionnaire was received

2. Applications and product profiles.

=> First and line extension procedures (n=62)

In 2002, the 62 procedures were distributed as follows: o 5 line extensions (all pharmaceuticals for companion animals). o 57 first procedures.

The number of applications for products containing new active ingredients has considerably decreased over recent years; there was none in 2002. Non-standard applications (25/57) represented 44% of the first procedures, split between generic (13), bibliographic (5) and informed consent (7) applications (see Table 1).

The number of first applications for livestock products (37; 63%) was higher than for companion animals (22; 37%). The 43 pharmaceuticals are split between livestock products (23) and companion animal ones (19), with an additional product for use in both. The 14 procedures for vaccines were all for livestock, except 1, and 1 for both food-producing and companion animals (see Table 2).

Table 1: First procedures in 2002: type of applications

Standard Non-standard

NAI* Fixed

combination Normal Informed

consent Generic Biblio.

Total

Pharmaceuticals 0 1 17 7 13 5 43

Vaccines - 0 14 0 0 0 14

Total 0 1 31 7 13 5 57

* New Active Ingredient

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Table 2: First procedures in 2002: type of products and target animals

Livestock Companion Combined use

Pharmaceuticals 23 19 1

Vaccines 12 1 1

Total products 35 20 2

=> Repeat use procedures (n=25)

The 25 repeat use procedures represented 29% of all procedures in 2002. They were mainly for pharmaceutical products, evenly split between livestock (10) and companion animals (12); 2 were generic and 2 bibliographic applications. The 3 repeat use procedures for vaccines were all for food-producing animals.

3. Involvement of the Member States. 3.1 Involvement as RMS:


In 2002, the involvement as RMS was distributed as follows: the UK acted as RMS the most with 20 procedures (32%), including 6 procedures referring to a product at 4 strengths for dogs and 2 for cats. Ireland followed with 13 (21%) procedures, mostly generic products. Then came France with 12 (19%), Germany 10 (16%) and Italy and Spain with 2 each (3%); Belgium, Denmark and Sweden were involved in 1 procedure each (2%). In 2002, Belgium and Spain acted for the first time as RMS in a MRP. The number of procedures per RMS is summarised in Table 3 and Figure 1. The reason for choice of RMS mainly was a positive previous experience with the national agency.

Table 3: The RMSs since 1995

RMS: BE DE DK ES FR IR IT NL SE UK Total

‘95-‘98 1 0 3 0 0 8 1 1 0 0 7 20

1999 1 0 6 1 0 7 0 0 0 1 7 22

2000 2 0 4 1 0 11 5 7 3 0 10 41

2001 2 0 4 1 0 7 12 1 2 5 5 37

2002 2 1 10 1 2 12 13 2 0 1 20 62

Total 1 27 4 2 45 31 11 5 7 49 182 1: survey sample 2: first procedures and line extension


In 2002, the involvement as RMS for repeat use procedures was distributed as follows: the UK acted as RMS the most with 9 procedures; then followed by Italy with 5, France and Germany with 3 each, Ireland 2, and Denmark, the Netherlands and Sweden with 1 each. The number of procedures per RMS is summarised in Table 4 and Figure2.

Table 4: The RMSs for repeat use procedures since 2000

RMS DE DK FR IR IT NL SE UK Total

2000 3 0 0 0 1 0 0 2 6

2001 0 0 0 0 0 1 0 2 3

2002 3 1 3 2 5 1 1 9 25

Total 6 1 3 2 6 2 1 13 34

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3.2 Involvement as CMSs:


All 15 member states, plus Iceland and Norway, were involved as CMS in one or more procedures, from 1 procedure for Iceland, up to 41 for the Netherlands. The 62 procedures represented a total of 471 involvements as CMSs.

The average number of CMSs per procedure was higher than in 2001: from 6 to 8 (including those rejected, cf. 9 in 2000); the average number of procedures per country also was higher from 13 in 2001 up to 28 in 2002 (cf. 18 in 2000). The involvement of each member state in the 62 procedures is summarised in Table 5 and Figure 1.

A breakdown of the type of applications and the average number of CMSs per procedure shows a significant difference between normal applications and line extensions versus bibliographic, generic and informed consent dossiers (see Table 6).

Table 5: Total involvement of the MSs in 2002 (repeat use procedures excluded)

AT BE DE DK EL ES FI FR IR IT LU NL PT SE UK IC NO TOTAL

RMS 0 1 10 1 0 2 0 12 13 2 0 0 0 1 20 0 0 62

CMS 37 30 37 31 27 33 23 26 38 29 31 41 26 24 26 1 11 471

Figure 1: Total involvement of the MSs in 2002 (repeat use procedures excluded)

0

10

20

30

40

50

60

AT BE DE DK EL ES FI FR IR IT LU NL PT SE UK IC NOMember States

Num

ber o

f pro

cedu

res

CMS

RMS

Table 6: Average number of CMSs per procedure in relation to the type of application in 2001 and 2002 (repeat use procedures excluded)

2001 2002

Type of procedures Number of procedures

Average number of CMSs

Number of procedures

Average number of CMSs

Normal 14 8 28 10

Line extension 1 1 5 9 Full

Bibliographic 10 8 5 2

Generic 11 3 13 4

Ab

rid

ged

Informed consent - - 7 5

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All member states, except Iceland, were involved in the 25 repeat use procedures. This gave an average of 2 CMSs per procedure (cf. 1 in 2001), ranging from 1 to 7. For a total involvement of the MSs in the repeat use procedure, see Figure 2.

Figure 2: Total involvement of the MSs in the repeat use procedures in 2002

0

2

4

6

8

10

12

14


Num

ber

of p

roce

dure

s

CMS

RMS

3.3 Reasons for choice of CMSs:


For most applicants, commercial interest motivated the choice of CMSs. For generic applications, the choice was based on the countries where the pioneer products were registered.

On exclusion of CMSs, the following reasons were given: § For 1 minor species product for honeybee, the excluded CMSs were those where honeybee

treatment is not considered as a veterinary medicine (Belgium, Portugal). § Countries that required national translation of complete Part I (Italy and Spain). § Agency for which fees were considered too high (UK). § Stringent national requirements on intravenous products (the Netherlands). § For teat dips, countries where distribution problems occur, when the General Sale List system

(GSL) does not apply.


The reasons for choice of CMSs were as follows: § Countries not selected for the first procedure, and which have since demonstrated interest in the

product, were obviously chosen. § For 3 applications, it was due to failure of the first procedure with the chosen countries, so the

dossier was resubmitted via repeat use. § For already nationally registered product, the repeat use procedure also was an opportunity to

harmonise SPC and facilitate further variations.

4. National assessment procedures by the RMSs. => First and line extension procedures:

For most procedures, both RMSs and applicants rated respectively the dossier and the assessment report either good or excellent; only efficacy data were deficient in one dossier and a bibliographic one was lacking pharmacokinetics data.

Applications whose validation in the MRP occurred within 6 months after authorisation by the RMS (n=12) were surveyed on the time taken to evaluate the original dossier. On average, the national assessment took 7.5 months, from 3 up to 23 months, with a 7-months clock-stop for the latter (see Table 7). Although the average duration of the national approval process appears relatively short, there

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are disparities in the average time between normal applications, which require a longer evaluation period, and non-standard applications, as would be expected. Some delays also occurred with 1 bibliographic application, due to inaccuracies in the RMS assessment report on the required content for such dossiers (see Table 8).

Table 7: National assessment procedure by the RMS (n=12)

Table 8: National assessment procedure by the RMS in relation to the type of applications

Type of procedure Number of procedures

Minimum (months)

Maximum (months)

Average length of total procedure (months)

Normal 5 3 23 9.9

Line extension 1 - - 7.7

Bibliographic 2 3 9.4 6.2

Generic 2 3 6.4 4.7

Fixed combination 1 - - 4.5

Informed consent 1 - - 3

5. Validation (n=58)

In 6 applications, representing 37 CMSs procedures, there were 9 objections raised by France, Germany, the UK and Portugal. For 1 of these 6 applications, validated in the end, the objections were on the content of the dossier: 3 CMSs required a TSE declaration (DE, PT, UK), and 1 CMS an electronic SPC (DE). For the other 5 applications, a total of 6 CMSs’ procedures were not validated (see Table 9): § For 2 generic dossiers, there was concern by one CMS (FR) on the withdrawal period being

different to the one for the reference product. For one of them, the reference product was also not authorised in the country of application according to Community provisions (DE).

§ For another generic dossier, the non-validation was due to the proposed SPC, as approved by the RMS, being different to the one for the innovator product in the CMS (FR). The issue was further discussed during the VMRFG discussion and all other MSs were in agreement that the application should have been validated.

§ For 2 fixed combination procedures, the issue related to the criteria to comply with such an application. For 1 dossier France objected but it was Spain who did not validate in the end. The other procedure solely involved 1 CMS (UK) and is therefore not reported in all subsequent sections (number of questions, VMRFG discussion...) which are not relevant to this procedure as there was no other CMS to pursue with the MR.

Table 9: Rejection at validation per CMS in 2002 (repeat use procedures excluded)

AT BE DE DK EL ES FI FR IR IT LU NL PT SE UK IC NO Total

CMS 37 30 37 31 27 33 23 26 38 29 31 41 26 24 26 1 11 471

Rejections 0 0 1 0 0 1 0 3 0 0 0 0 0 0 1 0 0 6

% 0% 0% 3% 0% 0% 3% 0% 12% 0% 0% 0% 0% 0% 0% 4% 0% 0% 1%

Months clock

running Months clock

stopped Total procedure

length (months)

Average 5 2.5 7.5

Maximum 16 7 23

Minimum 3 0 3

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The repeat use procedures (n=20) were all validated with the CMSs not raising any objections.

6. Number of questions per CMS.


The overall average number of questions per procedure and per CMS has increased from 7 in 2001 to reach 9 again in 2002, same as in 2000. The average number of questions ranged from 0.1 (Luxemburg) to 19 (France) (see Table10). As a question can trigger a related SPC question, the number of SPC and non-SPC questions are shown separately.

France has considerably reduced its number of questions over the past 3 years (see Figure 3). The only other CMSs showing a clear trend are Spain and Portugal which showed a significant increase.

Table 11 shows the relation between the type of application and the average number of questions per CMS. We observe that in 2002 bibliographic procedures were the most subject to questions.

Table 12 shows the relation between the type of product (pharmaceutical, vaccine, companion and food animal) and the average number of questions per CMS, with the highest for vaccines and livestock products.

Figure 3: Average number of questions per CMS: annual trend since 2000 (repeat use procedures excluded)

0

5

10

15

20

25

30

35

40

45


Ave

rage

num

ber

of q

uest

ions

200020012002

Table 10: Average number of questions per CMS in 2002 (repeat use procedures excluded)

AT BE DE DK EL ES FI FR IR IT LU NL PT SE UK NO Overall

Average SPC 0.4 3.4 6.2 2.8 0.7 6.8 6.1 5.3 6.8 0.7 0 3.4 8.9 6.9 5.5 0.6 n.a.

Ave. non SPC 0.9 5.1 5.7 3.8 0.7 10.1 4.9 13.6 5.5 1.2 0.1 2.9 6.3 3.5 12.2 0 n.a.

Average all 1 9 12 7 1 17 11 19 12 2 0.1 6 15 10 18 0.6 8.8

Minimum all 0 0 0 0 0 0 1 2 0 0 0 1 0 1 3 0 n.a.

Maximum all 7 31 35 23 5 59 19 54 32 6 3 27 34 24 36 3 n.a.

n.a.: not available

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Table 11: Average number of questions per CMS in relation to the type of applications since 2001 (repeat use procedures excluded)

2001 2002

Type of application


Average number of questions



Normal 14 7 28 10

Bibliographic 10 8 4 15

Generic 11 6 13 8

Table 12: Average number of questions per CMS in relation to the type of products since 2001 (repeat use procedures excluded)

2001 2002

Type of product Number of procedures




Pharmaceutical 28 7 43 7

Vaccine 8 8 14 14

Companion animal 6 8 24 7

Food animal 30 7 35 11


The overall average number of questions per procedure and per CMS was quite low (3). The countries that asked the highest number of questions were Denmark and the UK with an average of 7 questions per dossier.

7. Number of questions per procedure and per dossier part.


Applicants were still asked a significant number of questions per procedure, with an overall average of 65 (cf. 80 and 40 in respectively 2000 and 2001). This ranged from 1 question for 2 generic procedures, up to 256 for a normal application for a vaccine involving 15 member states.

When looking at the distribution by category, 18% were minor questions, 36% major questions and 46% SPC questions (see Table 13 and Figure 4), with an average of 41 SPC questions to normal dossiers against only 16 to generics. As in previous years, most major questions related to the Part II (quality) (37%) and Part IV (efficacy) (40%) of the dossier (see Table 14 and Figure 5).

Table 13: Number of questions by category in 2002

Average Min. – Max.

Major 24 0 – 151

Minor 11 0 – 47

SPC 30 0 – 86

Figure 4: Questions by category in 2002

SPC46%

Major36%

Minor18%

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Table 14: Number of major questions by dossier parts in 2002

Average Min. – Max.

Major part I 0 0 - 8

Major part II 9 0 - 70

Major part IIIA 5 0 - 52

Major part IIIB (n=43)

1 0 - 4

Major part IV 10 0 - 47

Figure 5: Major questions by dossier part in 2002

I1%

IIIA20%

IIIB2%

IV40%

II37%


Applicants were asked an average of 3 questions per procedure, ranging from 0 to 28 for a dossier for a vaccine. Most questions focused on Part IV of the dossier (78% of the major questions) and on the SPC (43% of the total questions).

8. VMRFG Discussion.


In order to solve the objections raised by the CMSs, a VMRFG discussion was necessary for 35 of the 57 procedures, i.e. 61%, like in 2001.

The CMSs raised objections on the following: § Quality, Safety and Efficacy. § User safety. § Ecotoxicity. § SPC. § For generic applications: requirements for bioequivalence studies. § For vaccine dossiers: duration of immunity and non-compliance with a European

Pharmacopoeia monograph.

For 29 of the 35 procedures (83%) where a VMRFG discussion was necessary, most CMSs that had raised objections attended the meetings. In most cases, the RMSs directly informed the applicants of the outcome of the discussion and all problems were solved in 8 of the 35 (23%) discussions. As a result, and in order to avoid arbitration, applicants withdrew from one or more CMSs in 19 of the 27 procedures (70%) where problems remained unsolved (see Table 15); this corresponded to 46 withdrawals from 12 CMSs. In the 8 procedures where problems remained, applicants did not withdraw and considered arbitration in 7 of them (see 9.2 Arbitration p.15).

Table 15: Performance of the VMRFG discussion and annual trend

2002 (n=35/57)

1999 (n=18/22)

2000 (n=26/35)

2001 (n=24/39) n %

Procedures where CMSs who raised major objections attended:

44% 68% 83.5% 29 83%

Procedures where applicants were immediately informed by the RMSs of the outcome:

100% 96% 100% 32 94%

Procedures where all problems were solved: 72% 16% 37.5% * 8 23%

Procedures with unsolved problems where applicants withdrew in one or more CMS:

50% 68% 100% 19 70%

* For one procedure all the problems were not solved during VMRFG discussion, but they all were by day 90

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A VMRFG discussion was necessary in 2 of the 20 repeat use procedures, i.e. 10%. One discussion took place to solve a disagreement between the RMSs and the CMSs; the other was to discuss implementation of a variation to the SPC, resulting from a major question.

9. Withdrawals from the CMSs and arbitration.

9.1 Withdrawals:

=> First and line extension procedures (reasons on n=57, figures on n=62)

The reasons for withdrawals were fairly similar to the ones reported in the previous years: § Quality, Safety and Efficacy. § Requirements for ecotoxicity data. § Generic: requirements for bioequivalence studies. § Bibliographic: data requirements for such dossiers. § Vaccine: non-compliance with a European Pharmacopoeia monograph under revision (this

led to withdrawals from all 3 CMSs).

Table 16 and Figure 6 show the evolution of the percentage of total withdrawals, and per CMS since 2000. For total involvement and success rates per CMS in 2002, refer to Table 17 and Figure 7.

Most withdrawals occurred for normal and bibliographic applications (see Table 18).

Table 16: Summary table on percentage of withdrawals per member state since 2000


2000 (n=41)

0% 17% 18% 50% 7% 0% 14% 42% 8% 5% 0% 4% 0% 70% 6% N.A. 25% 13%

2001 (n=37)

0% 42% 8% 0% 6% 4% 0% 0% 0% 0% 0% 17% 0% 0% 33% 0% 0% 7%

2002 (n=62)

3% 20% 11% 19% 0% 3% 30% 12% 8% 0% 3% 22% 0% 21% 12% 0% 0% 10%

Figure 6: Evolution of the percentage of rejections at validation and withdrawals since 2000

2%

4%

1%

13%

7%

10%

0%

2%

4%

6%

8%

10%

12%

14%

2000 (n=41) 2001 (n=37) 2002 (n=62)

Rejected

Withdrawn

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Table 17: Involvement as CMSs and success rates in 2002 (n=62 – repeat use excluded)


Total as CMS 37 30 37 31 27 33 23 26 38 29 31 41 26 24 26 1 11 471

Rejected 0 0 1 0 0 1 0 3 0 0 0 0 0 0 1 0 0 6

% 0% 0% 3% 0% 0% 3% 0% 12% 0% 0% 0% 0% 0% 0% 4% 0% 0% 1%

Withdrawn 1 6 4 6 0 1 7 3 3 0 1 9 0 5 3 0 0 49

% 3% 20% 11% 19% 0% 3% 30% 12% 8% 0% 3% 22% 0% 21% 12% 0% 0% 10%

Approved 36 24 32 25 27 31 16 20 35 29 30 32 26 19 22 1 11 416

% 97% 80% 86% 81% 100 94% 70% 77% 92% 100 97% 78% 100 79% 85% 100 100 88%

Table 18: Withdrawals in relation to the type of applications in 2002

Type of application


Number of CMSs procedures

% of withdrawals

Normal 28 276 14%

Bibliographic 4 7 14%

Generic 13 52 10%

Figure 7: The success rates per CMS in 2002 (n=62 – repeat use excluded)

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Figure 8: The success rates per CMS for repeat use procedures in 2002 (n=25)

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9.2 Arbitration in the first and line extension procedures:

For commercial reasons, applicants only considered arbitration in 9 of the 35 procedures where a VMRFG discussion did not resolve all the questions. In countries where applicants had a low commercial interest and in order to avoid unnecessary delays to the launch of a product on the key markets, the applicants generally preferred withdrawing, as arbitration can be a long process. For a honeybee product, it was also important not to lose the 2003 season market.

Although 9 applicants considered taking the procedure to arbitration, 4 did not pursue due to the risk of delaying or even losing their licence in all the other CMSs that approved the dossier.

In the end, the arbitration process went ahead for 5 procedures (cf. 1 in 2001). For 2 generic applications, the only CMS (Belgium) questioned the adequacy of plasma-based study to demonstrate bioequivalence to the pioneer product for 2 antiparasitics. The CVMP validated the referral in March 2002 and endorsed the view that the available data were sufficient to prove bioequivalence in June, i.e. 3 months later, including clock stops; a positive Commission decision followed 3 months later in September. From the time it was referred to the CVMP, the arbitration procedure lasted for 6 months.

For 3 line extensions (1 product at 3 different strengths), 2 CMSs out of 13 (Denmark and Spain) questioned the risk benefit of the proposed higher dose in the treatment of skin and associated soft tissue infections. The procedure was initiated in October, and the CVMP delivered a positive opinion to market in January 2003, i.e. 3 months later. The Commission decision in favour to market was delivered on 16th April, thus the whole process lasted for 6 months.

10. Post day 90: sending translations and issuing licences.


Translations:

The dates when applicants sent translations to CMSs were available in 78% of cases (n=288/371) (cf. 96% and 89% in respectively 2000 and 2001). 20% were simply not available at the time this report was prepared and the remaining 2% were missing for the following reasons: § Translations not required (n=4) § Delayed by the applicant who had no intention to market (n=2) § Awaiting patent expiry (n=1)

The average number of days taken by the applicants to send translations to each CMS was 32 (cf. 19 and 33 days in respectively 2000 and 2001). In 46% of cases (n=136), translations were sent within 15 days of Day 90. However, in 35% of cases (n=103), it took over 30 days to do so (see Table 19).

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The average time to send translations for full applications was 31 and 35 days for respectively normal and bibliographic dossiers (cf. 30 and 32 in 2001); it took 29 days for generic applications (cf. 46 in 2001) (see Table 20).

Licences:

The dates licences were issued were available in 79% of cases (n=293/371), which gives a fair representation. For procedures where day 90 fell towards the end of 2002, dates were not available at the time of preparing this report (n=67). The release of the remaining 11 licences was delayed for the following reasons: § Delays by applicant in sending translations (n=3) § Staff changes/restriction in some national agencies (n=7) § Awaiting publication of a monograph (n=1)

The average time to obtain a national licence after translations have been received was 57 days like in 2001 (cf. 48 days in 2000). Calculations were made from day 90 (n=42) in cases where translations were already sent by that day. Of the 293 dates reported, 34% were within the 30 days recommended in the Best Practice Guide. However, there might have been clock stops which are not taken into account in these calculations; these can occur when companies have been advised to correct the translations and the CMS is waiting for the revised text. Only Austria and Germany, like in 2001, were able to issue licences within an average of 30 days. Other countries varied, from 40 for France up to 130 days on average for Belgium (see Figure 9).

The average time to issue a bibliographic licence was slightly higher than for a normal or a generic dossier (see Table 20).

Total post day 90 timeline:

The total average time from Day 90 to obtaining a licence was 89 days (32+57) (cf. 67 and 90 days in respectively 2000 and 2001).

Table 19: Time period post day 90 in 2002

Days to send translations Days to issue licences

Average days 32 57

Min. - Max. days 0 - 216 0 - 276

% with data 78% 79%

Distribution of the data

>= 30 days 103 (35%) >= 60 days 99 (33%)

15 - 30 days 54 (18%) 30 – 60 days 95 (32%)

=< 15 days 136 (46%) =< 30 days 99 (34%)

Table 20: Time to obtain a licence in relation to the type of applications since 2001


Average days to send translations

Average days to issue licences Type of

application 2001 2002 2001 2002 2001 2002

Normal 14 28 30 31 50 61

Bibliographic 10 4 32 35 80 74

Generic 11 13 46 29 29 63

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Figure 9: Average days for the CMSs to issue licences after receipt of final translations in 2002.

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n 29 13 25 14 16 25 10 14 25 16 21 26 20 12 19 8

=> Repeat use procedures

There were not enough available data to report.

11. Functioning of the procedures and major problems reported.

11.1 Performance of the RMSs: the applicants’ view

On the whole, applicants were fairly satisfied with the RMSs’ performance on all aspects: availability, support and in keeping them informed of the evolution of the procedure.

Only in one procedure the applicant felt the RMS (UK) should have made more effort at day 54 to obtain the list of questions from 1 CMS (Austria), which appeared difficult to get in touch with.

In 3 line extension applications, there was a contentious issue between the RMS (UK) and the CMSs on the content of the SPC. Some CMSs required both existing and new indications and these had to be produced in the end.

In another procedure, the RMS (IT) was felt a bit slow in forwarding the questions from the CMSs, and did not attend the VMRFG discussion.

It must be stressed that in 2002, 3 applicants used the MRP for the first time and 2 were really pleased with the support they received from the RMSs (France: application for a minor species product and Germany: bibliographic dossier). The other applicant felt more guidance could have been provided by the RMS (UK) on the requirements for a bibliographic dossier, which caused major delays in the start of the procedure.

For repeat use procedures, all applicants were generally satisfied with the RMSs.

11.2 Performance of the applicants: the RMSs’ view

On the whole, the RMSs were very pleased with the applicants’ performance on all aspects: communication, availability, transparency and commitments to provide detailed responses to the list of questions.

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Two of the 3 “first time user” applicants made considerable efforts to improve the quality of their dossier; the other one, involved in 2 bibliographic procedures, was not rated so well due to some misunderstandings from the start of the procedure on the requirements for such dossiers. On repeat use procedures, no major problems were reported.

11.3 Performance of the CMSs:

The view of the RMSs :

The procedures generally functioned well between the RMSs and the CMSs, with most CMSs respecting the timeline to forward their list of questions, stimulating the discussion and raising useful questions, e.g. user safety, target animal safety.

Some CMSs however delayed sending in their comments and differences in interpretation of bioequiva lence occurred. Eudratrack was not always fully completed by all CMSs, as reported every year. Sections 5.Validation and 8.VMRFG discussion of this report provide a comprehensive list of issues raised by the CMSs.

Repeat use procedures, especially those refused during the first round, functioned well.

The view of applicants:

Applicants were generally satisfied with the procedures. A few applications however faced some difficulties:

In 1 procedure, although the applicant was pleased with the 11 CMSs unanimously adopting a positive strategy on environmental risk management, Germany subsequently refused it and the application was withdrawn. A post-procedure discussion with the national authority however stressed that the German environmental agency, and not the BgVV, was actually opposed to this strategy.

For 1 bibliographic dossier, submitted by a first time user, there were some different views on the requirements for the content of such dossiers.

Other difficulties reported: - Some CMSs that raised questions did not attend the VMRFG discussion. - 1 CMS refused to grant a licence at day 90 without having raised any questions. - Differences in interpretation of “pharmacologically active”. - Technical problem with e-mail submission, which cannot cope with very large file s.

12. Proposals for improvement.

12.1 From the RMSs:

The RMSs emphasised the necessity for all CMSs to follow the Best Practice Guide, i.e. respect the timeline (forward objections prior to the meeting), attend the VMRFG discussion and complete Eudratrack.

The lack of harmonisation in interpretation of guidelines and monographs was also mentioned as in previous years.

The following proposals for improvement were put forward by the RMSs:

To introduce a legislation on minor species and minor indications.

For repeat use procedures, when CMSs raise major objections: => Invite the CMSs involved in the first procedure to the VMRFG discussion.

12.2 From the Applicants:

Applicants also emphasised the need for the CMSs to follow the BPG, especially for all CMSs raising objections, to attend the VMRFG discussion.

They also stressed the importance for the CMSs to better adhere to the “MR philosophy”, especially for procedures for product already marketed in other EU countries and with long safety record. For

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instance, an applicant initiated a procedure for a vaccine in response to the need expressed by practitioners in one country and to prevent illegal import of the product in another. The dossier, although well defended by the RMS, was not approved by the CMSs and the applicant withdrew from all 3 CMSs; this was a very frustrating experience for both applicant and RMS.

The applicants put forward the following proposals for improvement to the MRP:

Objections at validation: the applicant should be given the opportunity to discuss these objections and the CMSs should provide clear reasons for not validating.

Time to answer the list of questions : => Possibility to extend the deadline when a significant number of CMSs are involved.

Lack of harmonisation between CMSs on interpretation of guidelines and monographs: => Introduce a majority vote at the end of the procedure, as already in practice for centralised applications. => Organise workshops for training of assessors.

=> English should be the language of choice for all parts of the dossier.

=> Introduce a fast track procedure for consequential variations to the SPC.

Arbitration: => Option to have licences issued in the CMSs raising no objections and to follow through to arbitration with the CMSs that still do.

On specific types of dossier:

Line extensions : the VMRFG could issue some guidance on the specific changes to the therapeutic indications for a marketing authorisation, which are regarded as new applications.

Generic dossiers : to harmonise, between MSs, the requirements for such dossiers and the SPC for pioneer products.

4. DISCUSSION

§ The applications profile:

In 2002, the number of applications considerably increased up to 87 (n=40 in 2001), with a significant number of repeat use procedures (n=25) chosen to overcome failed previous MRPs or harmonise SPCs to facilitate further variations. The shift towards pharmaceuticals was maintained with pharmaceuticals representing 70% of the applications (cf. 76% in 2001). On the other hand, the distribution between livestock and companion animals (respectively 56% and 44%) was more even than in 2001 (respectively 85% and 15%).

§ The RMSs and national timelines:

Belgium and Spain acted as RMS for the first time since 1998. Although only chosen due to the existence of a national licence in these countries, the applicants were pleased with their performance, which is encouraging and could influence the choice of RMS in the future. The number of procedures completed within the recommended maximum time of 210 clock days (7 months) increased up to 84% and the total length of the national assessment procedure, including clock stops, decreased to an average of 7.5 months (from 15.7 months in 2001), with 1 bibliographic dossier being however particularly slow (statistics based on 12 procedures).

§ The number of questions:

Although a decrease in the number of questions was noted in 2001, it rose again in 2002. This can be explained by the increase in the number of application for livestock products, which triggered more questions. As in previous years, the major questions focused on Part II and Part IV of the dossier and

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nearly half related to the SPC; this must however be interpreted carefully as the update of the numbering of SPC headings, as published in Dir. 2001/82 in December 2001, actually triggered many SPC questions.

§ The VMRFG discussion, withdrawals and arbitration:

The past trend of decreasing number of procedures needing a VMRFG discussion was not observed in 2002 (1999: 82%; 2000: 74%; 2001: 61% and 2002: 61%). However, the number of procedures not validated was considerably reduced (2001: 4%; 2002: 1%) showing that the quality of the dossier has improved. It is certainly encouraging to see that CMSs validated more dossiers and were prepared to discuss further objections dur ing the VMRFG meeting. This certainly accounts for why more discussions were required and consequently more withdrawals occurred (2001 7% and 2002 10%). Another encouraging sign in the resolution of objections was the increasing number of arbitrations (1 in 2001; 5 in 2002), with all outcomes in favour of the RMS assessments. This could further increase in the future if the proposal for automatic arbitration is adopted in the legislation. This would allow licences to be issued in the CMSs raising no objections and follow through to arbitration with the CMSs that still raise serious objections; this will also reduce the number of withdrawals.

§ Obtaining a national licence:

The average time from day 90 to obtaining a licence has not improved since 2000 (cf. 2000: 67; 2001: 90 and 89 in 2002). This certainly is an area where improvements would be welcomed, and requires both applicants and CMSs to respectively send translations and issue licences more rapidly. A longer post day 90 timeline was observed for bibliographic dossiers.

§ Areas of improvement since 1998:

It is important to note that some areas have certainly improved since the MR procedure was introduced and first surveyed in 1999, especially the attendance at the VMRFG discussion of CMSs rising objections, from 44% in 1999 to 83% in 2001 and 2002. As already discussed above under “The number of questions”, it is likely that the number of SPC questions has in fact decreased compared to 2001 as many were caused by the changes in headings (note that number of SPC questions are monitored separately from the total number only since 2001).

§ Proposals for improvement to the Mutual Recognition Procedure:

In addition to proposals for improvements, both RMSs and applicants stressed the importance for the CMSs to follow the BPG, which would certainly smoothen the procedure. This is all the more important since the BPG has been modified, to take effect in June 2003, with CMSs now having to raise questions by Day 54 instead of Day 55. According to the new BPG, the applicants still have only 11 days to answer the list of questions, but including 1 week-end instead of 2 (i.e. 9 working days + 1 week-end).

§ The future of the MRP:

It will be interesting to look at the impact of EU enlargement on this procedure. From another study, it came out that the CAVDRI simplified MR procedure, which is accepted by Slovakia, Hungary and the Czech republic, has not yet been used by any company. Only 2 companies are planning to use it for “repeat use” to extend existing mutually recognised products to the candidate countries. On the other hand, 20% of IFAH-Europe member companies intend to use the simplified procedure to voluntarily harmonise some of their candidate countries’ SPCs with the EU ones, and a similar number (25%) plan to include candidate countries in new MRPs before May 2004. It is therefore important that IFAH-Europe, jointly with the VMRFG, carries on running this survey to solve the current issues and to later focus on the problems and difficulties likely to arise with enlargement of the EU in May 2004.

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§ Comments from the VMRFG:

The VMRFG group dealt with a considerably increased number of applications in 2002. To accommodate the increase in 2003, more meeting time will be allocated. The procedures have worked generally well, and discussions have enabled the resolution of many questions. The attendance of relevant assessors or experts from CMSs raising questions always helps in resolving issues at Day 80 and should be encouraged. Some differences of interpretation between MSs still occur, and the VMRFG is taking steps to address these.

With respect to the submission of translations and the time taken to issue a national licence after Day 90, it should be pointed out that the total times recorded in this survey do not include clock stops while the applicant is preparing revised literature. The responsibility for reducing the time to authorisation rests with both the agencies and the applicants.

The VMRFG was pleased that the Czech Republic and Hungary were involved as CMS in some MR procedures in 2002 and that their participation functioned well. The marketing authorisations delivered in these 2 countries will remain valid at the time they enter the EU and no repeat use procedure will be required.

5. CONCLUSION

The mutual recognition procedure still functions reasonably well with some improvements noticed. It has evolved over the past 2 years with an increase in the number of dossiers taken to arbitration. Mainly bibliographic dossiers caused some difficulties in 2002, requiring more time for national assessment, to send translations and issue licences.

With 87 dossiers in 2002, the MRP remains the “top choice” procedure for registration of veterinary medicinal products across the EU. It must however be stressed that only a few of these applications might have been eligible for the centralised procedure, which recorded 5 registrations that year.

IFAH-Europe Contact: Sylvie Meillerais, Technical Coordinator Tel no.: +32 2 543 75 63 E-mail address: [email protected]

ifah-europe / vmrfg 2002 survey on the mutual …€¦ · the product profile: of the 87...

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