Report from the Commission on the experience acquired as a result of the operation of the procedures for granting marketing authorisations for medicinal products laid down in Regulation (EEC) N° 2309/93, in chapter III of directive 75/319/EEC and chapter IV of directive 81/851/EEC Report on the basis of Article 71 of Regulation (EEC) No 2309/93
Date: 2001-10-23
Institutions: European Commission
Subjects: market approval, marketing, marketing standard, medicinal product, pharmaceutical legislation, public health, veterinary medicinal product

COMMISSION OF THE EUROPEAN COMMUNITIES

Brussels, 23.10.2001
COM(2001) 606 final

REPORT FROM THE COMMISSION

on the experience acquired as a result of the operation of the procedures
for granting marketing authorisations for medicinal products laid down
in Regulation (EEC) N° 2309/93, in chapter III of directive 75/319/EEC
and chapter IV of directive 81/851/EEC

Report on the basis of
Article 71 of Regulation (EEC) No 2309/93

REPORT FROM THE COMMISSION

on the experience acquired as a result of the operation of the procedures
for granting marketing authorisations for medicinal products laid down
in Regulation (EEC) N° 2309/931, in chapter III of directive 75/319/EEC2
and chapter IV of directive 81/851/EEC3

Report on the basis of
Article 71 of Regulation (EEC) No 2309/93

I.

INTRODUCTION

Medicinal products are goods covered by the internal market principle of free movement of
goods, as has been confirmed by the Court of Justice on several occasions. Consequently,
Article 28 EC forbids all quantitative restrictions on imports and all measures having
equivalent effects between Member States. However, Article 30 EC allows prohibitions or
restrictions on imports, exports or goods in transit justified on certain grounds, including the
protection of health and life of humans and animals. On the basis of these provisions, the
Member States have enacted and maintained specific legislation on medicinal products for
human and veterinary use, thus restricting the free movement of these products in the internal
market.

In order to remove these obstacles to the internal market in pharmaceuticals while at the same
the Community has gradually
time ensuring a high level of public health protection,
developed a harmonised legislative framework for medicinal products. The first major
step was the adoption of Council Directive 65/65/EEC4 of 26 January 1965 stipulating, inter
alia, that a medicinal product may only be placed on the market in the European Union after a
marketing authorisation has been granted. By now, this Directive has been amended several
times. Step by step, the framework was extended and refined by a great number of legal acts,
including, with regard to medicinal products for human and veterinary use:

• Directive 75/318/EEC on the particulars and documents accompanying an application for

marketing authorisation5,

• Directive 75/319/EEC containing important substantial and procedural provisions,

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2

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4

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Council Regulation (EEC) n° 2309/93 of 22 July 1993 laying down Community procedures for the
authorisation and supervision of medicinal products for human and veterinary use and establishing a
European Agency for the Evaluation of Medicinal Products, OJ L 214, 24.8.1993, p. 1.
Second Council Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down
by Law, Regulation or Administrative Action relating to proprietary medicinal products, OJ L 147,
9.6.1975, p. 13.
Council Directive 81/851/EEC of 28 September 1981 on the approximation of the laws of the Member
States relating to veterinary medicinal products, OJ L 317, 6.11.1981, p. 1.
Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by
Law, Regulation or Administrative Action relating to proprietary medicinal products, OJ B 22,
9.2.1965, p. 369.
Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of Member States
relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the
testing of proprietary medicinal products, OJ L 147, 9.6.1975, p. 1.

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• Directive 89/105/EEC on issues of prices and reimbursement6,

• Directive 89/342/EEC on immunological medicinal products7,

• Directive 89/343/EEC on radiopharmaceuticals8,

• Directive 89/381/EEC on medicinal products derived from human blood or human

plasma9,

• Directive 91/356/EEC on good manufacturing practice10,

• Directive 92/25/EEC on the wholesale distribution11,

• Directive 92/26/EEC on the classification for the supply of medicinal products12,

• Directive 92/27/EEC on the labelling and on package leaflets13,

• Directive 92/28/EEC on the advertising of medicinal products14,

• Directive 92/73/EEC on homeopathic medicinal products15,

• Directive 81/851/EEC relating to veterinary medicinal products,

• Directive 81/852/EEC on the particulars and documents accompanying an application for

marketing authorisation for veterinary medicinal products16,

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Council Directive 89/105/EEC of 21 December 1988 relating to the transparency of measures
regulating the prices of medicinal products for human use and their inclusion in the scope of national
health insurance systems, OJ L 40, 11.2.1989, p. 8.
Council Directive 89/342/EEC of 3 May 1989 extending the scope of Directive 65/65/EEC and
75/319/EEC and laying down additional provisions for immunological medicinal products consisting of
vaccines, toxins or serums and allergens, OJ L 142, 25.5.1989, p. 14.
Council Directive 89/343/EEC of 3 May 1989 extending the scope of Directives 65/65/EEC and
75/319/EEC and laying down additional provisions for radiopharmaceuticals, OJ L 142, 25.5.1989,
p. 16.
Council Directive 89/381/EEC of 14 June 1989 extending the scope of Directives 65/65/EEC and
75/319/EEC on the approximation of provisions laid down by law, regulation or administrative action
relating to proprietary medicinal products and laying down special provisions for medicinal products
derived from human blood or human plasma, OJ L 181, 28.6.1989, p. 44.
Commission Directive 91/356/EEC of 13 June 1991 laying down the principles and guidelines of good
manufacturing practice for medicinal products for human use, OJ L 193, 17.7.1991, p. 30.
Council Directive 92/25/EEC of 31 March 1992 on the wholesale distribution of medicinal products for
human use, OJ L 113, 30.4.1992, p. 1.
Council Directive 92/26/EEC of 31 March 1992 concerning the classification for the supply of
medicinal products for human use, OJ L 113, 30.4.1992, p. 5.
Council Directive 92/27/EEC of 31 March 1992 on the labelling of medicinal products for human use
and on package leaflets, OJ L 113, 30.4.1992, p. 8.
Council Directive 92/28/EEC of 31 March 1992 on the advertising of medicinal products for human
use, OJ L 113, 30.4.1992, p. 13.
Council Directive 92/73/EEC of 22 September 1992 widening the scope of Directives 65/65/EEC and
75/319/EEC on the approximation of provisions laid down by law, regulation or administrative action
relating to medicinal products and laying down additional provisions on homeopathic medicinal
products, OJ L 297, 13.10.1992, p. 8.
Council Directive 81/852/EEC of 28 September 1981 on the approximation of the laws of the Member
States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of
testing of veterinary medicinal products, OJ L 317, 6.11.1981, p. 16.

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• Directive 90/677/EEC on the extension of the Community provisions on veterinary

medicinal products to include immunological products17,

• Directive 91/412/EEC on good manufacturing practice for veterinary medicinal products18,

• Directive 92/74/EEC on homeopathic veterinary medicinal products19,

• Regulation (EEC) n° 2377/90 on maximum residue limits for veterinary medicinal

products in foodstuffs of animal origin20.

the progress in terms of completing the single market

Despite this legislation,
in
pharmaceuticals was not satisfactory. In the beginning of the 1990s, it was therefore decided
to fundamentally improve the authorisation procedures. A new system was established with
the adoption of Regulation (CEE) n° 2309/9321 as well as a number of Directives22 amending
the existing legislative framework. This new system entered into force in 1995 and is based
on two separate procedures for the granting of marketing authorisation for a medicinal
product:

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19

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The centralised procedure23
leads to a single marketing authorisation valid
is granted in the form of a Commission
throughout the whole Community. It
decision, which is based on a scientific evaluation by the committees created within
the European Agency for the Evaluation of Medicinal Products (EMEA)24. This
procedure is mandatory for certain medicinal products developed by means of
biotechnological processes. Over and above that, the procedure is optional for certain
other categories of medicinal products, inter alia those presented for an entirely new
indication constituting a significant innovation, new medicinal products derived from
human blood or human plasma or those containing a new active substance which had

Council Directive 90/677/EEC of 13 December 1990 extending the scope of Directive 81/851/EEC on
the approximation of the laws of the Member States relating to veterinary medicinal products and laying
down additional provisions for immunological veterinary medicinal products, OJ L 373, 31.12.1990,
p. 26.
Commission Directive 91/412/EEC of 23 July 1991 laying down the principles and guidelines of good
manufacturing practice for veterinary medicinal products, OJ L 228, 17.8.1991, p. 70.
Council Directive 92/74/EEC of 22 September 1992 widening the scope of Directive 81/851/EEC on
the approximation of provisions laid down by law, regulation or administrative action relating to
veterinary medicinal products and laying down additional provisions on homeopathic veterinary
medicinal products, OJ L 297, 13.10.1992, p. 12.
Council Regulation (EEC) n° 2377/90 of 26 June 1990 laying down a Community procedure for the
establishment of maximum residue limits of veterinary medicinal products in foodstuffs of animal
origin, OJ L 224, 18.8.1990, p. 1.
Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the
authorisation and supervision of medicinal products for human and veterinary use and establishing a
European Agency for the Evaluation of Medicinal Products, OJ L 214, 24.8.1993, p. 1
Council Directive 93/39/EEC of 14 June 1993 amending Directives 65/65/EEC, 75/318/EEC and
75/319/EEC in respect of medicinal products, OJ L 214, 24.8.1993, p. 22; Council Directive 93/40/EEC
of 14 June 1993 amending Directives 81/851/EEC and 81/852/EEC on the approximation of the laws of
the Member States relating to veterinary medicinal products, OJ L 214, 24.8.1993, p. 31; Council
Directive 93/41/EEC of 14 June 1993 repealing Directive 87/22/EEC on the approximation of national
measures relating to the placing on the market of high- technology medicinal products, particularly
those derived from biotechnology, OJ L 214, 24.8.1993, p. 40.
For the different phases of this procedure see flow chart no 1 in the annex.
Established by Article 49 paragraph 1 of Regulation 2309/93.

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not been authorised by the 1st January 1995 by any Member State for use in a
medicinal product.

For those medicinal products, not eligible for the centralised procedure or where the
applicant chooses not to follow the centralised procedure, the new system provides
for a mutual recognition procedure25. Where eligible, this procedure has to be used
by the applicant whenever an application for marketing authorisation for a medicinal
product concerns two or more Member States. Within this procedure, the competent
authority of one Member State, the so-called Reference Member State, carries out the
scientific evaluation. The other Member States concerned by an application for the
same product shall recognise the evaluation of the Reference Member State. A
Concerned Member State may however raise objections where it considers that there
are grounds for supposing that the authorisation of the medicinal product may
present a risk to public health. In this case, all the Member States concerned by the
application shall use their best endeavours to reach an agreement on the issue. If they
fail, the matter is referred to the EMEA where an arbitration procedure is followed.
The arbitration leads to a Commission decision addressed to the Member States
concerned by the matter, which have to implement the necessary provisions.

The Commission adopted two Communications, 94/C82/0426 and 98/C201627 with a view to
better specifying the scope of both procedures and to interpret the provisions dealing with
procedural aspects.

When establishing this new system, it seemed appropriate to make sure that it could be
evaluated in due course. Article 71 of Regulation 2309/93 therefore obliged the Commission
to report on the experience acquired as a result of the operation of the two authorisation
procedures within six years of the entry into force of the Regulation. An obligation to review
the newly established legislative framework was not laid down, intentionally leaving open the
possibility of follow-up based on the results of the evaluation.

During the preparation of this report it appeared necessary to extend the evaluation and the
reflections on necessary legislative amendments not only to the authorisation procedures, as
envisaged in Article 71 of Regulation 2309/93, but also to other aspects of the pharmaceutical
legislation. The main reasons to consider other aspects of the pharmaceutical legislation are
based on the development of science and technology, certain positions taken by the European
Parliament (reports) and/or by the Council (conclusions or resolutions), and more generally
the evolution of the European society. The scope of the report has consequently been
extended to the whole regulatory system established by the pharmaceutical legislation.

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For the different phases of this procedure see flow chart no 2 in the annex.
JO C 82, 19.3.1994, p. 4.
JO C 229, 22.7.1998, p. 4.

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II.

THE NEW AUTHORISATION PROCEDURES – EVALUATION AND REVIEW PROPOSALS

As already mentioned, Article 71 of Regulation (EEC) n° 2309/93 provides for the obligation
for the Commission to publish a general report on the overall functioning of the system. In
particular the objective of this report is to evaluate the experience acquired as a result of the
operation of the centralised and the mutual recognition authorisation procedures laid down in
this Regulation, in Chapter III of Directive 75/319/EEC (medicinal products for human use)
and in Chapter IV of Directive 81/851/EEC (medicinal products for veterinary use) after six
years of operation.

II.1.

Experience with the system since 1995

In order to gain a comprehensive and objective picture of the experience with these
procedures made by all parties concerned such as the national authorities, industry, patients
and health professionals, the Commission asked an independent consultant to systematically
investigate the general experiences. This approach aimed to guarantee a better basis for an
appropriate and unbiased report on the overall functioning of the new marketing authorisation
procedures.

II.1.1. Evaluation by external consultants

the Commission concluded a contract with CMS Cameron McKenna and
In 1999,
Andersen Consulting for
the two authorisation
procedures28. The task was to review the regulatory processes and the telematics systems in
place and to analyse the extent to which the results achieved over the period from 1995 to
1999 have met the objectives set out in the legislation.

the evaluation of

the operation of

Between February and August 2000, extensive consultations and interviews were held by
the consultants. Questionnaires and interviews covered the regulatory authorities responsible
for authorising medicines for human and veterinary use. A series of interviews were carried
out within the EMEA to get an insight into detailed operation of the centralised procedure and
the role of the EMEA. The chairmen of the CPMP29, CVMP30, MRFG31 and VMRFG32 were
interviewed in order to review practical issues, which have arisen from the operation in the
new systems. The marketing authorisation holders who had used the centralised procedure
were invited to participate by completing a detailed questionnaire concerning their most
recent experience of using the system and by taking part in follow up interviews on issues
raised in the questionnaire. According to the same methodology a large sample of marketing
authorisation holders who had used the mutual recognition procedure was selected for
conducted with all major
questionnaires and interviews. Group discussions were
pharmaceutical associations upon a range of issues arising from the two procedures.
Ministries in the Member States, responsible for health, social affairs, finance and agriculture
were sent written questionnaires, seeking their opinions upon issues such as evaluation of the
safety of medicinal products and access to market. A selective number of regulatory
authorities responsible for authorising medicines in candidate countries were also approached.
Ministries in candidate countries responsible for health, social affairs, finance and agriculture
could also give an opinion upon issues such as evaluation of safety and access to market.

28

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32

Contract PSR/99/502316.
CPMP: Committee for Proprietary Medicinal Products.
CVMP: Committee for Veterinary Medicinal Products.
MRFG: Mutual Recognition Facilitation Group.
VMRFG: Veterinary Mutual Recognition Facilitation Group.

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Professional associations responsible for the regulation of doctors, dentists, pharmacists and
veterinary practitioners were sent written questionnaires, seeking the comments of those
prescribing, dispensing or administering medicinal products on issues such as transparency,
the assessment of safety and the availability of medicines. Patient associations were invited to
together with associations
participate in two ways. National consumer organisations,
representing a broad spectrum of disease areas and countries of establishment were sent
written questionnaires, asking for their views on issues such as the authorisation and the
availability of new medicines. In addition, the questionnaire was placed on the website of the
Commission service responsible for the pharmaceutical legislation33 to provide the interested
associations with the opportunity to send in their contributions.

The final report, referred to hereafter as Cameron McKenna Andersen report, was published
in October 2000. It is available on the website cited above34. For details on the evaluation
done by the external consultants and their findings, reference is made to this report.

II.1.2

Further information and statistics

In addition to the analysis of Cameron McKenna/Andersen, the Commission organised and
participated in various workshops and public hearings on the evaluation of the existing
legislation and possible legislative amendments. These workshops and hearings involved the
participation of Member States representatives, European associations in the area of
pharmaceuticals as well as other interested parties. All oral and written remarks of Member
States as well as industry, health professionals, consumers and patients have been carefully
considered.

When evaluating the overall development and success of the existing procedures and their
development, further facts and statistics have to be taken into consideration. Unless
otherwise indicated, these figures relate to the period between 1995 and 2001:

a)

Statistics relating to the EMEA

To contribute to the protection and promotion of public and animal health, the EMEA has to
mobilise scientific resources from throughout the European Union to provide high quality
evaluation of medicinal products, to advise on research and development programmes and to
provide useful and clear information to users and health professionals. It is also important to
develop efficient and transparent procedures to allow timely access by patients to innovative
medicines through a single marketing authorisation, as well as to control the safety of
medicines for humans and animals, in particular through a pharmacovigilance network and
the establishment of safe limits for residues of veterinary medicines in food of animal origin.

To manage these tasks, the EMEA has continuously expanded. This is reflected in the
in 200135 and
significant increase in the budget, from 6 813 085 ECU in 1994 to 62 152 000
also in the increasing EU subsidies to the EMEA budget36. The amount of these subsidies has
changed over the years. Starting with a subsidy of 6 800 000 ECU in 1994 there are, since the
year 2000, in addition to the general annual subsidy, special contributions from EEA-EFTA
states and a special one voted by the EU budgetary authority for orphan medicinal products.
€
, the special orphan subsidy
The general subsidy for the year 2001 amounts to 14 000 000

€

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http://pharmacos.eudra.org.
Under the address http://pharmacos.eudra.org/F2/pharmacos/docs/Doc2000/nov/reportmk.pdf.
See table 1 on “EMEA budget evolution” in the annex.
See table 2 on “EU contribution to EMEA budget” in the annex.

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€
. The EEA-EFTA state contribution amounts to 250 000

€
amounts to 1 300 000
. In general,
the relative part of the EU contributions to the EMEA budget has decreased continuously over
the years37. Whereas in 1996 (starting up phase), the percentage was about 47 %, it had
decreased to less than 23 % in 2001.

In line with the significant expansion of activities the staff of the EMEA has continuously
increased38. All the staff working at the EMEA have the status of temporary agents under the
EU staff regulations. There are no permanent officials, but some additional interim staff and
national experts. The number of people in post rose from 50 (as of 31.12.1995 with
17 externals) to 194 (as of 31.12.2000 with 3 national experts and 13 externals).

b)

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Statistics on the two procedures39

Apart from the medicinal products for which it is mandatory (Part A of the Annex to
Regulation (EEC) n° 2309/93), the centralised procedure has been extensively used
for medicinal products for which it is optional (Part B of the same Annex).

For medicinal products for human use, from 1995 to 2000 inclusive, 97 applications
were filed under Part A and 182 applications under Part B for a total of
279 applications40. For medicinal products for veterinary use, from 1995 to 2000
inclusive, 18 applications were filed under Part A and 21 applications under Part B
for a total of 39 applications41. After the granting of a marketing authorisation, the
applicant can apply for extensions or variations of the marketing authorisation
already granted. The figures contained in table 5 and 6 of the annex give a complete
picture on the applications, variations and extensions, withdrawals by the applicants
before the end of the procedure and opinions given by the CPMP and CVMP.

For medicinal products for human use, from 1995 to May 2001, 171 have been
authorised, 2 have been suspended and 12 revoked42. Some revocations are made
upon request of the marketing authorisation holder but suspensions or revocations are
generally linked to pharmacovigilance issues. For the centralised procedure, as well
as for the mutual recognition procedure, the number of variation applications is
increasing dramatically. In the centralised procedure, from 1995 to 2000, 816 type I
variations (minor variations) and 385 variations type II (major variations) have been
processed.

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See table 3 on “Percentage of EU contributions to EMEA budget” in the annex.
See table 4 on “Staff evolution (number of posts)” in the annex.
Regarding veterinary medicinal products, the figures show that the evolution of the new system points
to an initial reluctance on the part of the pharmaceutical companies to get acquainted with and use the
centralised and mutual recognition procedures. The small size of the market of veterinary medicinal
products has also to be taken into consideration.
See table 5 on “Centralised procedures (human medicinal products)” in the annex.
See table 6 on “Centralised procedures (veterinary medicinal products) in the annex.
See table 7 on “Centralised procedure: Figures on Marketing Authorisations granted by the European
Commission (status in 5/2001)” in the annex.

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For medicinal products for veterinary use, from 1995 to May 2001, 26 have been
authorised and 1 has been suspended43. No authorisations have been revoked. For
these products, it has to be indicated that relatively few variations to the marketing
authorisations have been processed (57 type I and 6 type II). The number of
extensions to marketing authorisations was 9 and one abridged application has been
authorised after informed consent from the original marketing authorisation holder.

The mutual recognition procedure, as far as medicinal products for human use are
concerned, has been used for medicinal products like generics, extensions of
marketing authorisations already granted, medicinal products having followed the
"concertation procedure" which was in place before the entry into force of the
centralised procedure as well as for medicinal products containing new active
substances.

From 1995 to 2000, 988 procedures have been finalised44.

Concerning most particularly medicinal products containing new active substances
and taking into account only those for which the centralised procedure is optional,
since 1995 until 2000, 113 applications were made through the centralised procedure
and 73 through the mutual recognition procedure45.

For the mutual recognition procedure, as well as in the centralised procedure, the
number of variation applications is increasing dramatically. In the mutual recognition
procedure, 2 183 type I variations and 1 096 type II variations have been processed46.

Concerning medicinal products for veterinary use, the number of mutual recognition
procedures has increased significantly since the 1st January 1998 when the mutual
recognition procedure became compulsory for the majority of the different types of
pharmaceutical products47. Whereas in 1996 and in 1997 there were only 13,
respectively 16 mutual recognition procedures concluded, the number rose to 31 in
1999 and 32 in 200048. It is difficult to discern any specific trend, although the
majority of the products in the mutual recognition procedure are not innovative. The
centralised procedure and the mutual recognition procedure were both used to a
similar extent for authorisation of innovative products, excluding biotechnological
products (List A) subject to a compulsory assessment in the centralised procedure.
Concerning most particularly medicinal products containing new active substances
for which the centralised procedure is optional, from 1995 to 2000, 20 applications
were made through the centralised procedure and 14 followed the mutual recognition
procedure49.

See table 7 on “Centralised procedure: Figures on Marketing Authorisations granted by the European
Commission (status in 5/2001)” in the annex.
See table 9 on “Mutual recognition procedure (human medicinal products)” in the annex.
See table 11 on “Applications for human medicinal products with new active substances submitted
under the centralised procedure and the mutual recognition procedure since 1995” in the annex.
See table 9 on “Mutual recognition procedure (human medicinal products)” in the annex.
Article 8a of Directive 81/851/EEC, as modified by Council Directive 93/40/EEC of 14 June 1993
amending Directives 81/851/EEC and 81/852/EEC on the approximation of the laws of the Member
States relating to veterinary medicinal products, OJ L 214, 24.8.1993, p. 31.
See table 10 on “Mutual recognition procedures (veterinary medicinal products since 1996) in the
annex.
See table 12 on “Applications for veterinary medicinal products with new active substances submitted
under the centralised and the mutual recognition procedure since 1995” in the annex.

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45

46

47

48

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Where mutual recognition cannot be achieved or where there is a lack of
harmonisation between decisions taken by the Member states for a particular
medicinal product or where the interests of the Community are involved, referrals to
the EMEA can be made. For medicinal products for human use, from 1995 to
May 2001, 21 referral procedures have been completed concerning 33 medicinal
products50. For medicinal products for veterinary use, from 1995 to May 2001,
3 referral procedures have been processed51.

II.2.

Assessment and review proposals

II.2.1 General remarks

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In assessing the overall success of the two authorisation procedures, the answers
received during the various consultations made by the external consultant as well as
by the Commission depend on a number of objective and subjective factors,
including the differing perceptions and interests. Indeed, very often widely differing
views were expressed on a concrete issue, making it impossible to determine a
consensus or even to identify a more general tendency. The views of regulators and
industry are frequently different and relatively polarised. The views of different
regulators often vary as noticeably as the views of different companies. On several
key issues, such as the adjustments that need to be made to the mutual recognition
and centralised procedures, there is less consistency in the views expressed by
regulators (particularly in relation to long-term strategy for regulation) than in the
views of industry.

Stemming from the findings of the assessment, this part of the report indicates also
the lines to be taken when amending the existing pharmaceutical legislation. In doing
so, the report will describe the general approach to be followed where changes are
needed, but it will not refer to individual and concrete provisions, which will be
elaborated in the explanatory memorandum of the relevant legislative proposals.

As a way of general consideration on the future legislative proposals described
below, the review of the pharmaceutical legislation has to pursue a set of four major
objectives:

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To ensure a high level of public health protection for the European citizen, in
particular by allowing rapid access to innovative and safe products and by tight
market
control and
pharmacovigilance. With regard to veterinary medicinal products, the level of
protection of animal health should be improved in particular by increasing the
number of medicinal products available.

surveillance, based on reinforced procedures of

To further complete the internal market in pharmaceuticals and to establish a
regulatory framework favourable to the competitiveness of European
pharmaceutical
consideration aspects of
taking
globalisation.

industry, while

into

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To meet the challenges of an enlargement of the European Union.

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51

See table 8 on “Community referral procedures” in the annex.
See table 8 on “Community referral procedures” in the annex.

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To rationalise and to simplify, as far as possible, the system and to improve its
global coherence, its visibility and the transparency of the procedures.

These corresponding and intrinsically linked goals can be realised optimally only if
the review achieves a sound overall equilibrium between all of them. This requires
a Community system that is dynamic, consistent, and efficient and provides for a
proper balance between the centralised and decentralised systems. In general, the
evaluation of the existing authorisation procedures has proven that the system in
place since 1995 works well and has contributed to achieving a high level of public
health protection as well as progressing the internal market in pharmaceuticals in
Europe. As a consequence, there is no need to fundamentally change the current
system with its dual structure.

The following indications on how to further improve the regulatory framework of
pharmaceuticals in Europe can therefore be limited to optimisation and amendment
of the present procedures, while keeping their general structure. Unless otherwise
specified,
the following observations apply both to human and to veterinary
medicines.

II.2.2 Overall results

When the new system was designed in the early 1990s, the basic assumption was that the
same fundamental objectives would apply to both procedures, namely to ensure a high
level of public health protection and to contribute to the completion of the internal market in
medicinal products. The success of the two procedures has to be measured against these goals.

With regard to the first objective, the evaluation by the external consultant in line with the
views of the Commission allows the conclusion that both systems have succeeded in
ensuring a high level of public health protection and, in particular in the human sector, an
increase availability of innovative medicinal products. Both systems have provided a high
degree of quality, safety and efficacy for medicinal products made available for human beings
and animals. The requirements with regard to the three fundamental criteria of medicinal
products laid down in the existing legislation ensured a high level of public health protection.

However, the degree to which the two procedures have contributed to the completion of the
internal market in pharmaceuticals differs considerably. It is unanimously recognised the
positive impact on the free movement of pharmaceuticals of the centralised procedure. This
procedure has worked efficiently and the concept of a Community authorisation did not meet
significant problems in practice. On the contrary, the mutual recognition procedure did not
function as expected, as explained in detail below. The idea of a mutual recognition of
scientific evaluation of one Member State by the competent authorities of the other Member
States has been realised only to a certain extent.

A positive effect of both procedures has been that the availability of new medicines has
increased over the last five years, in particular in the sector of medicinal products for human
use. Criticism however focused on the length of time between an application and the final
marketing authorisation, which was claimed to be excessive in some cases. Further concern
related to situations where a medicinal product was authorised but not effectively put on the
market or, after a certain time on the market, was withdrawn. Problems also occurred with
regard to veterinary medicinal products where it is feared that the availability of medicinal
products for food producing animals decreases as a result of the introduction of the
requirements to establish maximum residue limits.

11

An overall assessment of the two authorisation procedures in terms of cost-benefit is difficult.
The procedures have not yet produced real dividends in terms of cost efficiencies through
economies of scale. Still, there is a need to reduce the administrative burden where this does
not have public health implications. Similarly, there is a certain perception that the renewals
of marketing authorisation are less and less based in practice on a scientific re-evaluation, but
appear to be a simple administrative procedure. This situation causes financial burdens to the
marketing authorisation holders and is resource consuming for the competent authorities
without adding to the protection of public health. In terms of cost efficiencies, it also has to be
the
considered that national authorities are under significant resource pressure and that
funding of the decentralised system, and indirectly of the centralised system, by national
authorities is an increasing cause for concern in some Member States.

There is a strong demand, supported both by national authorities and marketing authorisation
holders, for greater transparency of the authorisation procedures. To improve the current
situation, a Community level initiative is generally preferable to divergent solutions in each
individual Member State.

Certain criticism was also made to the system on the handling of generic medicinal pro-
ducts. The current legislative obligation for the applicant of the generic medicines to use the
same procedure taken by the reference medicinal product, together with the provisions
relating to the data exclusivity protection period, amounts to significant obstacles for generic
medicines.

On the whole, it should be noted that the principal structure of the system operating since
1995 is well-balanced, sound and has produced satisfactory effects. The system could
contribute towards ensuring a high level of public health protection, supporting the
development of European pharmaceutical industry, and – to a different extent – to further
harmonising the internal market of pharmaceuticals. As a consequence, there is a widespread
consensus that both procedures have their specific merits and contributions to the fundamental
objectives of the pharmaceutical system and for this reason should be kept in parallel, even if
improved in individual aspects.

II.2.3. Centralised procedure

• Scope

According to the results of the Cameron McKenna Andersen report, there is a general
opinion within marketing authorisation holders and Member States that
the centralised
system is capable of working well with a high level of satisfaction. There also is general
recognition of the very considerable contribution made by the EMEA to the successful launch
of the system. The EMEA is viewed as well managed and having discharged effectively all
the functions allotted to it by legislation.

The procedure has proven its effectiveness for biotechnology medicinal products, and made
biotechnology processes fully acceptable in the pharmaceutical sector. The scientific
innovation on which new kinds of medicinal products using complex techniques are based
(e.g. gene therapy) makes European evaluation, based on pooling the best scientific skills
from national agencies, even more necessary.

12

The Community-level evaluation requires a high level of expertise. By using both the national
resources provided by Member States and the necessary external experience (i.e. a network of
approximately 2 300 experts), the EMEA ensures that the quality of the scientific evaluation
is fully satisfactory.

Nevertheless, the Commission considers that, in order to boost competitiveness by helping
innovative companies and to cope with foreseeable future evolution in terms of innovation
and technical progress, the scientific profile of the EMEA should be reinforced by providing
additional scientific support and by specifying and expanding some of its tasks. In order to
achieve this, an increased and flexible scientific expertise is needed – which could be
developed either in the framework of scientific specialised expert ad hoc groups and in-house
advisory structures or by establishing communication channels with experts from the
scientific community outside the Agency.

A significant number of companies and Member State authorities are in favour of the
centralised system being opened up to a broader range of products. This is a good indicator
of the general level of confidence in the principles underlying the system and the advantages
that it can bring.

The Commission considers, in the light of scientific developments during the last 6 years,
that the list of products for which the centralised procure is mandatory does not correspond to
the needs of the market for medicinal products and to the need for a unique scientific
assessment. The decentralised procedure is not adequate for authorisation of medicinal
products containing new active substances, taking into consideration the high costs for their
development as well as the effects on society when those products are only placed on the
market of a limited number of Member States. This last fact (lack of homogeneity of the
Community market) will probably become even more a cause for concern after the
enlargement of the European Union. This observation applies also to the products included in
list B of the Annex, which is considered inadequate and rather narrow, especially in the case
of other innovative products and of generic medicinal products.

1. List A of the Annex to Regulation 2309/93 should be maintained and it should still
be mandatory for the products referred to in it to be authorised through the
centralised procedure.

2. The centralised procedure should become mandatory for all new active substances, i.e.
any substance, which has not been part of an authorised medicinal product in any of
the Member States.

3. The centralised procedure should be open, on an optional basis, to any other product
provided for which the applicant shows that
the product constitutes a significant
innovation or that there is a Community interest, for patients and from animal
health point of view, in respect of the granting of an authorisation under this
procedure. Along these same lines, an authorisation under this procedure should also be
possible for immunological veterinary products subject to Community prophylactic
measures.

4. This procedure should be optional in the case of generic medicinal products of centrally

authorised reference products.

13

• Authorisation procedure

The development of new technologies is viewed as posing new challenges that justify a
review of the assessment procedures of the CPMP. Some further flexibility is needed to
provide solutions in two situations, which are currently not covered by the regulation. On the
one hand, the cases where the availability of a given product is indispensable for reasons of
public health. On the other hand, the fact that very often certain patients could obtain and
have at
their disposal certain medicines, which are not covered by an authorisation
(compassionate use). Both situations can have negative consequences on public health if no
guidance is provided at Community level regarding the conditions of use, or on public
confidence if patient needs in the various Member States are not addressed in a fair and
equitable way.

The Commission agrees that the assessment procedure is, in some cases, not rapid enough. In
the case of innovative products, slow developments in the procedure might neutralise the
beneficial effects that the placing of the market of innovative products might have on society.
It also recognises the need to accelerate the part of the procedure dealing with the final
decision process.

1. The different steps for the authorisation procedure should remain basically the same

for both human and veterinary medicinal products.

2. The authorisation procedure should be accelerated. This could be achieved by

shortening some deadlines in the different steps of the procedure.

3. Along the same lines accelerated assessment procedures (fast track procedures) should
be foreseen for medicinal products of major interest from the point of view of public
health and therapeutic innovation.

4.

In some cases, conditional authorisation, to be re-evaluated on a yearly basis should be
made possible; the possibility of an authorisation under exceptional circumstances will
be maintained under the conditions already described in the existing legislation.

5. Regarding compassionate use of medicinal products for human use according to which
patients may have at their disposal certain medicines, before authorisation is granted, the
EMEA should be able to adopt recommendations to be applied by Member States within
their own administrative framework. These recommendations would aim mainly at
establishing the conditions for this compassionate use to be put into practice

There is also margin for improvement as far as transparency is concerned, in both respects,
regarding information on the product characteristics and the assessment reports on the
medicinal products, as well as the reasons and the documentation on which a decision on
granting or refusing an authorisation is based. Greater transparency would make the
procedure more easily accessible and easier to understand for all interested parties and would
facilitate an even smoother and more rapid handling of marketing authorisation applications.

14

Transparency rules should be improved regarding the dissemination by the Agency of the
documents on which the authorisation decision is based by publishing the assessment reports,
the opinions delivered by the committees and the conclusions reached in case of appeal. A
general transparency requirement could be added in order to ensure that any interested person
may have access to the summary of product characteristics, the assessment report on the
medicinal products and the parts of the file and documents which are not of confidential
nature.

Another factor which, under the current circumstances, creates an important administrative
burden for marketing authorisation holders and adds to the workload of the Agency is the
renewal requirement for marketing authorisations every five years. It is not perceived as
the appropriate way of assessing that the medicinal product effectively meets the requirements
for its authorisation. It is more appropriate to substitute reinforced surveillance system to a
continuous
and supervision
requirements should be strengthened in order to respond to the need to guarantee the
objective of public health protection in that context. The duties of the marketing authorisation
holders should also be reinforced. Their obligation to record and report to the Member States
should not remain limited to all suspected serious adverse reactions but be expanded to any
other suspected serious adverse reactions of which they may reasonably be expected to be
aware.

renewal. Pharmacovigilance

administrative

five-year

The marketing authorisation procedure does not allow precise administrative control on
whether effective use of marketing authorisations is made, especially in those cases where a
product, covered by an authorisation, is no longer on the market. In fact, there is no obligation
for marketing authorisation holders to inform the agency of the date when a product is placed
on the market.

1. The limits

regarding the validity of

the authorisation should be abolished;

authorisations should be valid for unlimited duration.

2. The marketing authorisation holder would have to make effective use of the marketing
authorisation, otherwise, if the product is not placed on the community market after a
certain period, the authorisation should cease to be valid.

3. The frequency for

in the context of
submission of periodic safety reports,
pharmacovigilance, should be reviewed – records should be submitted at shorter yearly
intervals (maximum three years) than the current five-year intervals.

4. The obligation to inform the Agency on the dates of actual marketing of the medicinal
product in the Member states or if the product ceases to be marketed should be
introduced.

• Decision making process within the centralised procedure

One of the most criticised areas of the centralised procedure is the decision-making process
that follows the scientific evaluation by the EMEA. The time length of this administrative
phase does not appear to be justified, in particular with regard to the general intention to
streamline and shorten the whole evaluation and authorisation process. To improve and speed
up the decision making process it is important to improve the rules in order to allow a faster
conclusion of the post-evaluation phase. However, apart from some internal improvements,
the time frames set out in Regulation (EEC) n° 2309/93 should be re-evaluated and if possible
be reduced.

15

Adaptations have to be included in the text of the regulation to ensure conformity with the
provisions of the new Council Decision 1999/468/EC52.

1. Member States will have a deadline of 15 days to react to the Commission proposal.

2. The regulatory procedure should be replaced by references to Articles 3 and 5 of
the consultation and management

Decision 1999/468/EC, which provide for
procedures.

The regulatory procedure should be only used in the context of technical modifications to the
legislation, in particular in the case of adaptation to scientific and technical progress of the
directive (basically the Annexes).

• EMEA

1.

Structure of the EMEA

The number of scientific committees of the EMEA does not reflect the current bodies
providing for the scientific assessment within the EMEA. Moreover, the composition of these
scientific committees needs to be reviewed in the light of the enlargement perspective for
example by reducing the number of representatives from two to one.

The Management Board, in its present form, needs to be reviewed to take into account the
future enlargement of the European Union. The new composition will also need to be in line
with the last proposals adopted by the Commission for the creation of the European Food
Authority as well as the two Agencies on Maritime and Air Safety. It has also to provide
sufficient guarantees that the interests of the civil society and industry are represented. The
current structure of the Management Board is not adequate in the context of modern
management and decision making theories to ensure representation of all interested parties.

On the same lines, and with the purpose of completing the whole coherence of the
administrative system of the EMEA, it seems appropriate to regroup all the national Heads of
Agencies in the form of an Advisory Board, which could give advice to the Commission and
to the executive director of the EMEA.

The Commission understands that the EMEA should be competent to give appropriate and
systematic scientific advice to companies aiming to actively participate in the innovation
process. This is the case in particular
for small and medium companies developing
biotechnological or innovative products for which scientific advice is crucial for the correct
and complete preparation of the scientific dossier.

52

Council Decision 1999/468/EC of 28 June 1999 laying down the procedure for the exercise of
implementing powers conferred on the Commission, OJ L 184, 17.7.1999, p. 23.

16

1. The structure of the EMEA needs to be completed in order to include the Committee for
Orphan Medicinal Products, set up under Regulation (EC) n° 141/200053 and the
Committee for Herbal Medicinal Products, which will be set up by a new Directive on
traditional herbal medicinal products to be proposed soon.

2. An Advisory Board, composed of representatives of the national competent authorities,
which would have a consultative function with respect to the EMEA and the Commission
activities regarding authorisation procedures for pharmaceuticals, will be created.

3.

Increased flexibility should be introduced as regards the different expert groups that can
be created by the scientific committees and that form part of the EMEA. The possibility
of creating working parties and expert groups should be completed by procedures for
delegating certain tasks to these working parties. Also the creation of administrative
structures and specialised groups, with the participation, where necessary, of experts in
specific scientific fields, allowing for instance the development of scientific advice
procedures for the companies, should be envisaged. The possibility of using experts even
from outside the EU should not be excluded provided that guarantees regarding selection,
independence and qualifications are met.

4. The structure of the Management Board should also be reviewed to take into
consideration the future enlargement of the EU, the need for an adequate representation
of the civil society (patients, industry) and the proposed structure for the new Agencies
(Food Authority, Maritime Safety Agency and Air Safety Agency).

2.

Tasks of the EMEA

The scope of activities of the EMEA should be widened by inclusion of tasks, which go
beyond the evaluation of medicinal products in the context of the marketing authorisation.
This role as a scientific adviser will allow the Commission to request the EMEA scientific
advice on any issue regarding the authorisation of medicinal products.

Co-operation with the World Heath Organisation should be reinforced for the assessment of
certain medicinal products intended exclusively for the markets of third countries.

On the basis of the Commission’s experience in the field of parallel distribution, numerous
complaints as well as cases before the European Court of Justice, provide enough evidence
that action needs to be taken in that respect in order to prevent problems and ensure coherence
in the application of Community legislation.

Additional sanctions to the ones already included in the legislation, for instance financial
sanctions, to be imposed directly by the EMEA on the holders of market authorisation if they
fail to observe certain obligations laid down in connection with the authorisations, should be
considered. At this stage, the implication of the EMEA in imposing sanctions is not sufficient.
No financial sanctions are foreseen even if experience shows that most effective dissuasion is
achieved by applying financial penalties.

53

European Parliament and Council Regulation (EC) n° 141/2000 of 16 December 1999 on orphan
medicinal products, OJ L 18, 22.1.2000, p. 1.

17

1. The EMEA should contribute more actively in the framework of dialogues on

international harmonisation.

2. The possibility should be considered of giving the EMEA the task of ensuring that the
conditions laid down in Community legislation on medicinal products and in the
marketing authorisation are observed in the case of parallel distribution of medicinal
products authorised under the centralised procedure.

3. The committees forming part of the EMEA should play an increased role by assisting the
Executive Director of the EMEA and the Commission in drawing up, at their request, any
opinions on scientific matters concerning medicinal products.

4. A greater competence of the Commission when imposing sanctions is needed; the

competence to impose financial sanctions should be considered.

II.2.4. Mutual recognition procedure

• General assessment of the procedure

There is a clear acceptance and support for the mutual recognition procedure. The available
experience is limited, since the mutual recognition procedure was obligatory only from 1998
onwards. But even with this limited knowledge it is possible to conclude that the mutual
recognition procedure has contributed to a certain extent to the completion of the internal
market in pharmaceuticals while safeguarding a high level of public health protection.

The mutual recognition procedure with its possibility to include only a limited number of
Member States in the procedure, offers a flexibility that is important for those medicinal
products intended only for a restricted part of the European market, especially in the
veterinary sector. Many pharmaceutical companies, particularly the small- and medium-sized
enterprises, confirmed that the mutual recognition procedure meets their commercial needs
more effectively than the centralised system, since they do not have the resources to operate
on the entire European market. However, this has to be put in perspective with legitimate
patient needs to have medicinal products available in the different Member States.

Currently, there is a certain concern about the duration of the authorisation procedure,
which seems too long in general. However, the main problem with this procedure is that, in
practice the Member States too often do not recognise the marketing authorisation and the
scientific evaluation carried out by another Member State. Instead of relying on the evaluation
done by the Reference Member State, the competent authorities of the Concerned Member
States often make their own evaluation. This lack of true mutual recognition is confirmed by
the findings of the Cameron McKenna Andersen report.

Further problems are created by the current provisions concerning objections that may be
raised by the Concerned Member States to challenge the evaluation done by the Reference
Member State. The existing provisions allow such objections where the Concerned Member
State considers that there are grounds for supposing that the authorisation of the medicinal
product may present a risk to public health. This notion has not been defined in the
legislative provisions, thus leaving it open to a broad interpretation by the national authorities.
As a consequence, the notion of “risk to public health” is invoked in a number of situations
where it does not appear to be consistent with the idea of mutual recognition.

18

Once objections of public health have been raised, it often proves to be quite difficult to
reach an agreement between the dissenting Member States. The difficulties in reaching a
common solution were often linked to the fact that the Reference Member State, on the basis
of
its scientific evaluation, had already granted a marketing authorisation. From an
administrative and political point of view, it is more difficult to put into question a national
scientific evaluation when decisions have already been taken on the basis of this evaluation.

The informal groups on mutual recognition (MRFG and VMRFG)54 that have been
established to improve the operation of the mutual recognition procedure have worked with
remarkable success. They have contributed to the general improvement of the procedure and
in particular to the creation of a framework for the Member States to reach agreement on the
action to be taken in respect of applications where objections on public health grounds have
been raised. However, being informal groups with no legal basis, there has been some
concern about the legal effect of the groups’ work.

Finally, problems relate to the arbitration procedure, as confirmed by the Cameron McKenna
Andersen report. The intricacies of the mutual recognition procedure described above
continued to persist in the arbitration phase and, in particular the problem of how to deal with
a common interpretation of “risk to public health”. Further points, which made the arbitration
procedure particularly unattractive for the applicants, were the considerable duration of the
arbitration phase and the fact that during this phase the product could not be marketed in the
other Concerned Member States, even if they had been ready to grant the authorisation.

As a consequence, the applicant very often chose to withdraw the application from the
Member State, which had raised the objections. During the three years of the transitional
period from 1995 to 1997, when the mutual recognition procedure was not yet obligatory, 112
out of 249 new applications for human medicines that had been finalised through the mutual
recognition procedure, were finalised with at least one withdrawal, which is equal to 46 %. In
the years between 1998 and 2000, the figures were 223 out of 616 new applications, which
represents 36 %55. Despite this slight decrease, both figures show that there is a significant
problem. As a comparison, the numbers of arbitration procedures were extremely small. In
1997, there were only two arbitration procedures, one relating to a new application, one to a
type II-variation. In 1998, there was one arbitration procedure for a new application and four
arbitration procedures for type II-variations56.

The Commission as well as a certain number of national authorities is concerned by this
relation between withdrawals and arbitration procedures. By withdrawing the application
from a Member State that has raised the objections, the applicant prevents a thorough
evaluation of the objection raised and, accordingly, a Community-wide solution. Even if the
notion of “risk to public health” might sometimes have been invoked without a substantial
justification, some of the objections raised indeed justified a Community re-examination of
the scientific evaluation of the product.

54

55

56

See footnotes 31 and 32.
Figures based on the MRFG report “Analysis of Withdrawals in the Mutual Recognition Procedure” of
23.1.2001.
Figures based on the respective annual report of the MRFG. No figures on referrals for 1999 and 2000
are available.

19

1. First of all, concerning the duration of the national authorisation procedure, the
current deadline of 210 days should be reduced to 150 days of which 120 days will cover
the assessment report. By adding the duration of the mutual recognition procedure, the
total number of days will be comparable with the deadline of 210 days for the centralised
procedure.

2. As regards the procedure itself, different modalities should be foreseen depending on
whether or not the medicinal product is already authorised in a Member State. Where the
medicinal product is already authorised, the mutual recognition phase has to be based on
the existing authorisation. Where the medicinal product is not yet authorised, the Member
States concerned with an application should agree on the scientific evaluation report
before any authorisation is given.

3.

4.

It is necessary to better specify the concept of risk for public health, as referred to in the
legislation, in order to prevent the mutual recognition procedure from being stopped.

In order to facilitate the smooth running of the procedure, it seems appropriate to give a
formal and legal status to the existing MRFG/VMRFG. Their responsibilities should
concern in particular the part of the procedure dealing with the objections based on the
concept of risk for public health.

5. During the arbitration phase, which involves the EMEA, it appears necessary to ensure
that the objections related to the serious risk for public health are evaluated properly and
the application
that necessary follow-up measures are taken,
withdrawal. In order to further harmonise the level of public health protection resulting
from the arbitration procedures, it seems desirable to extend the Commission decision to
the significant dissatisfaction with the length of the
all Member States. To meet
arbitration procedure,
the time limits should be re-evaluated and, where possible,
shortened.

independently of

• Pharmacovigilance and supervision

Taking into consideration the fundamental objective of the achievement of the highest level of
public health protection, the legislative framework for the follow-up of pharmacovigilance
measures has not been totally satisfactoryfrom a Community perspective even though this has
not caused an issue from a public health point of view.The current provisions on
pharmacovigilance allow Member States,
to suspend a marketing
authorisation in their territories, without ensuring the necessary follow-up at Community
level.

in case of urgency,

The existing pharmaceutical legislation contains provisions on the control of quality and on
good manufacturing practices, which only cover the finished product, and not the active
substances used as starting materials for medicinal products. Experience has shown that
this limited approach is not always adequate because the quality of a finished medicinal
product is linked to the complete process from manufacturing of the starting materials until
the final manufacturing of the product.

20

1. To further improve and harmonise the level of safety of medicinal products, new
provisions should be established to make sure that urgent action taken by one Member
State is thoroughly evaluated on a European level and that, where necessary, appropriate
measures are taken by all Member States.

2. The Commission should be empowered to lay down detailed guidelines on the
manufacturing of active substances used as starting materials for medicinal products
and to establish the obligation to use only those active substances as starting materials
that have been manufactured in compliance with these guidelines.

3. The system of inspections should also cover the control, under specific conditions, of

active substances used as starting materials.

II.2.5.

Specific issues

Apart from the points outlined above, the evaluation of the system for authorisation of
medicinal products also points to a need for changes to the existing legislation on the
following specific issues:

• Definition of medicinal products

The current definition of a medicinal product for the purposes of the pharmaceutical
legislation is worded in a way that could not cover certain new or future forms of medical
treatment, in particular those related to gene therapy and cell therapy. There is a clear need for
a regulatory framework, both predictable and sustainable, for these new therapies. For reasons
of coherence and effectiveness, it appears best to include these treatments in the existing
framework rather than to establish a separate set of rules.

The definition of medicinal product (definition “by function”) should be modified to include
new therapies.

• Generic medicinal products

The experience of the past shows that certain problems have occurred with regard to generic
medicinal products. Whereas the incentives to develop innovative medicines should be
maintained and if possible improved, future legislation must at the same time lay down clear
rules for generic medicines that fulfil an equally important role within the health care system.
The legislation should provide for an optimal balance between innovative medicinal
products and generic medicines.

The possibility of preventing a generic medicinal product
from been authorised by
withdrawing the original product from the market should be excluded by appropriate wording
of the relevant provisions.

To avoid the scientific tests required to prepare a generic application being carried out outside
the Community for purely legal reasons, without having substantial influence on the access to
the market, it might be appropriate to introduce a provision allowing such kinds of activity
during the period of patent protection applied to the original product.

21

On the other hand, the different
levels of data protection for centrally and nationally
authorised medicinal products seems difficult to justify. Harmonisation of the time periods,
and the linkage between data protection for nationally authorised medicines and
corresponding patent protection, should therefore be re-considered. The experience in the
field of human medicinal products shows that there should be some kind of incentive to
further improve existing medicinal products, in particular to develop new and important
therapeutic indications. Such an incentive could be an additional data protection period.

1. Data protection periods should be harmonised with the period provided for the

centralised authorised products.

2. An extension of one year of data protection period could be allowed if a medicinal
product, covered by the normal data protection period, has developed a new therapeutic
indication with an important benefit for patients within the first 8 years of protection.

3. The term generic medicinal product should be introduced and defined in the legislation.

4. The possibility to prepare and to file a generic application during the period of patent

protection applied to the reference medicinal product should be introduced.

• Advertising of medicinal products for human use

There is a growing interest and knowledge among the general public for information on
medicinal products. In particular patients suffering from long-term diseases are looking for
information about possible treatments, using world-wide communication tools and especially
the Internet. Against this background, it seems appropriate to abandon the strict prohibition of
advertising of prescription-only medicines. However, with regard to the negative effects of an
abusive advertising, any new possibilities to disseminate information to the general public
should be subject to sufficient control mechanisms. These should include, apart from the
control by public authorities, a self-regulatory procedure under the surveillance of the same
authorities. When establishing such new possibilities of information, it should be considered
to limit them in a first experimental phase to certain therapeutic indications or diseases. After
sufficient experience has been gained on the effects in the different dimensions and the
procedures of control, it could be envisaged to further expand the scope of such provisions.

1. Specific information on request of patients or groups of patients should be authorised

for medicinal products subject to medical prescription.

2. As a first stage, and in order to evaluate the effects of such a measure, this information

would be allowed only for the treatment of three long-term/chronic diseases.

3.

Industry would need to adopt principles of good conduct as well as self-regulatory
control procedures, which will be agreed with the competent authorities.

4. After a certain period, the implementation of these provisions should be evaluated and if

necessary adapted.

22

• Homeopathic medicinal products

Since their entry into force, Directives 92/73/EEC and 92/74/EEC on homeopathic medicinal
products for human/veterinary use have achieved only a limited level of harmonisation. A
detailed analysis of their functioning is contained in the Commission Report to the European
Parliament and Council on the application of Directives 92/73/EEC and 92/74/EEC57. To
further improve the availability of these medicinal products and to move on in completing the
internal market for these medicines, it appears necessary to amend the relevant legislation. In
the area of veterinary medicine, homeopathic medicinal products intended for food producing
animals should also be eligible for the simplified registration procedure, in particular due to
their increasing use in organic farming.

1. The option for establishing a simplified registration procedure for certain homeopathic

medicinal products should be changed into an obligation.

2. As far as possible, simplified registrations granted by one Member State should be

recognised throughout the Community.

II.3.

Specific provisions concerning veterinary medicinal products and their
availability

The reduction of the available veterinary medicinal products for food producing animals
is an increasing problem58. The review of the pharmaceutical
legislation provides the
opportunity to address partly this issue.

legislation should provide incentives to enhance the interest of
The pharmaceutical
pharmaceutical firms in certain market segments by making the investments required prior to
the marketing more attractive.

An incentive not to focus only on the species that represent the most economically interesting
market should be granted. Considering the specific treatment needed for bees and fish and the
small market that these species represent, specific incentives should also be granted for
veterinary medicinal products for these species.

In addition, the use of existing medicinal products by practitioners should be facilitated. In
particular, in the absence of an authorised medicinal product for a specie and/or indication
concerned on their territory, Member States should allow the use by a veterinarian, in a food
producing animal, of a medicinal product available else-where in the Community under
conditions that will not endanger the protection of consumers and that will ensure information
to the owners and/or health professionals in their own language.

57

58

COM(1997) 362 final of 14.7.1997.
See Commission Communication of 5.12.2000, COM(2000) 806 final.

23

In addition, the active substances which enter in the composition of a veterinary medicinal
to toxicological and residue safety evaluation in order to set
product must be subject
Maximum Residue Limits (MRLs) according to Regulation 2377/90. The establishment of
MRLs is one factor, which has led the reduction of available medicines for food producing
animals. Therefore, the link between the two procedures would benefit from a clarification,
and the Commission intends to propose a review of this Regulation in the near future, to take
into consideration, among other issues, the issue of extrapolation from one species to another.

1. Specific provisions for veterinary medicinal products on the data protection period

could be set up.

2. The 10 years data protection period could be extended depending on the number of
animal species for which a firm would get a marketing authorisation (one year per
additional food producing species, up to a maximum of 13 years for 4 species or more).
This extension of the data protection period would only be valid if the granting or
extension of the marketing authorisation to several food-producing species is done within
3 years after the first marketing authorisation.

3. The provisions defining the conditions for using medicinal products for food-producing
species (“cascade” provision), which are not authorised in a certain Member State,
should be revised.

____________________

III.

CONCLUSIONS

1.

2.

3.

The two fundamental objectives underlying the existing pharmaceutical legislation
are to ensure a high level of public health protection while at the same time to
complete the internal market
in medicinal products. These major goals are
indispensable and need to be respected by all future pharmaceutical legislation.
Additional objectives however have to be taken into consideration, in particular those
necessary to meet the challenges of the forthcoming enlargement of the European
Union and to further promote the competitiveness of the pharmaceutical industry in
Europe.

It is proposed to keep the main principles and structures of the system for
authorisation of medicinal products for human and veterinary use, as put in place
in 1995. On the whole, they have proven appropriate and suitable for their purpose.
The credibility, sustainability and future success of the regulatory framework for
medicinal products in Europe will depend on the respect of these principles and
structures.

When further developing the pharmaceutical legislation, it has to be taken into
consideration that the pharmaceutical industry by developing new medicinal products
is significantly contributing to ensuring a high level of public health in Europe. The
necessary research and development requires considerable financial investments on
the part of the industry and quite often it takes up to fifteen years to bring a new
innovative product on the market. As a consequence, all amendments need to result
in a transparent, predictable and stable regulatory environment.

24

4.

5.

The optimal legislative framework in the area of medicinal products depends to a
large extent on the current state of play of the relevant branches of science, which are
developing rapidly. It
is proposed therefore to introduce in the pharmaceutical
legislation a certain degree of regulatory flexibility in order to allow a sufficiently
the technical requirements to the developing scientific
prompt adaptation of
knowledge.

With regard to the future enlargement of the European Union, an important part of
the future review proposals will be justified by the need to accommodate the system
to the increasing number of Member States, which will be involved in the
authorisation of medicinal products for the European market.

25

ANNEX

CENTRALISED PROCEDURE

- 4 months
Pre-submission
assistance

Optional any time before submission
Scientific advice

Day 15
Submission and validation

Day 70
Initial assessment considered

Day 120
List of questions and first conclusions

Clock stop for answers
by applicant

Day 180
Decision to hold hearing

Clock stop for hearing

Day 210
Opinion adopted

Day 240
Opinion (in all 11 EU languages)
and assessment sent to Commission

Day 300
Commission Decision

26

MUTUAL RECOGNITION PROCEDURE

Application to first Member State

210days

Assessmentreport
(includingSPC)

First Authorisation

Max.90days

Applicantrequestsmutualrecognition
ofthereferenceauthorisation

Update and issue of assessment report

(Parallel) applications
in other Member States

Maysuspendevaluation

Mutual Recognition Process

55days

No

Objections

Yes

MutualRecognition

Resolutionofissues

Clarification and dialogue
Point of view of applicant
(orallyorinwriting)

30days

No

Serious
objections
remain

Yes

Arbitration

90days
("clockstop"possibleforinputbyapplicant)

CPMP

Opinion

60days

Company Appeal

60days

Opinion (final)

Final National Decisions

Commission Decision

27

Table 1:

EMEA BUDGET EVOLUTION

YEAR

BUDGET IN EUROS (in Ecus until 1998)

1994

1995

1996

1997

1998

1999

2000

2001

6 813 085

14 412 000

22 550 000

28 530 000

31 900 000

42 650 000

55 287 000

62 152 000

Table 2:

EU CONTRIBUTION TO EMEA BUDGET
in Euros (in Ecus until 1998)

YEAR

Contribution

Special Orphan
contribution

EEA-EFTA

1994

1995

1996

1997

1998

1999

2000

2001

6 800 000

10 150 000

10 497 149

13 546 500

13 926 040

10 481 649

12 477 536

14 000 000

-

-

-

-

-

-

-

-

-

-

-

-

1 000 000

1 300 000

245 220

250 000

28

Table 3:

PERCENTAGE OF EU CONTRIBUTIONS TO EMEA BUDGET

YEAR

Contribution

Including special
Orphan contribution

Including contribution
from EEA-EFTA

1994

1995

1996

1997

1998

1999

2000

2001

99,80 %

70,42 %

46,55 %

47,48 %

43,65 %

27,57 %

22,56 %

22,52 %

24,37 %

24,62 %

24,82 %

25,01 %

Table 4:

STAFF EVOLUTION (Number of Posts)

YEAR

STAFF

DNE59

EXTERNAL STAFF

at 1.10.1994

at 31.12.1995

at 31.12.1996

at 31.12.1997

at 31.12.1998

at 31.12.1999

at 31.12.2000

2001

6

50

100

143

154

181

194

-

-

0

3

2

3

3

3

-

-

17

10

9

9

9

13

-

59

Detached national experts.

29

Table 5:

CENTRALISED PROCEDURES (human medicinal products):
(Figures on applications submitted in the EMEA from 1995 to 2000)60

1995-2000

Part A

Part B

Total

Applications submitted

Withdrawals

Positive CPMP opinions

Negative CPMP opinions61

97

12

64

1

182

37

112

3

1995-2000

Part A

Part B

Variations type I

Positive opinions, variations
type II

Negative opinions, variations
type II

Extensions (Annex II
applications)

265

159

0

34

551

224

2

20

279

49

176

4

Total

816

383

2

54

60

61

Parts A and B referred to lists A and B of the Annex to Regulation (EEC) n° 2309/93.
In case of appeal the opinion will not be counted twice.

30

Table 6:

CENTRALISED PROCEDURES (veterinary medicinal products):
(Figures on application submitted in the EMEA from 1995 to 2000)62

1995-2000

Part A

Part B

Total

Applications submitted

Withdrawals

Positive CVMP opinions

Negative CVMP opinions

Variations type I

Positive opinions, variations
type II

Negative opinions, variations
type II

Extensions (Annex II
applications)

18

3

11

0

Part A

14

2

0

0

21

2

26

0

1995-2000

Part B

43

4

0

9

39

5

37

0

Total

57

6

0

9

Table 7:

CENTRALISED PROCEDURE (Figures on Marketing Authorisations
granted by the European Commission (status in 05/2001)

AUTHORISED

SUSPENDED

REVOKED

Human medicinal product

Veterinary medicinal product

171

26

2

1

12

0

62

Parts A and B referred to lists A and B of the Annex to Regulation (EEC) n° 2309/93.

31

Table 8:

COMMUNITY REFERRAL PROCEDURES

Number of Community
Referral procedures
from 1995 to 05/2001

Number of concerned
medicinal products

Human medicinal product

Veterinary medicinal product

21

3

33

3

Table 9:

MUTUAL RECOGNITION PROCEDURES
(Human Medicinal Products)
(Number of mutual recognition procedures and variations from 1995 to 2000)

1995-1997

1998

1999

2000

TOTAL

Number of finalised
procedures

Variations type I
(minor variations)

Variations type II
(major variations)

249

166

253

180

339

222

253

306

988

671

1 007

2 183

301

320

1 096

Table 10:

MUTUAL RECOGNITION PROCEDURES
(veterinary medicinal products since)
(Number of mutual recognition procedures from 1996 to 2000)

1996

1997

1998

1999

2000

Total
5 years

Number of finalised
procedures

13

16

19

31

32

111

32

Table 11:

Applications for human medicinal products with new active substances63
submitted under the centralised procedure and the mutual recognition
procedure since 1995

Year

1995

1996

1997

1998

1999

2000

Total
6 years

Applications
centralised
procedure

Applications
mutual
recognition

% Centralised

% Mutual
Recognition

8

15

25

26

19

20

113

2

15

26

11

12

7

73

80 %

50 %

49 %

70 %

61 %

77 %

20 %

50 %

51 %

30 %

29 %

23 %

61 %

39 %

63

New active substance is any substance, which has not been part of an authorised human medicinal
product in any of the Member States by 1st January 1995.

33

Table 12:

Applications for veterinary medicinal products with new active
substances64 submitted under the centralised procedure and the mutual
recognition procedure since 1995

Year

1995

1996

1997

1998

1999

2000

Total
6 years

Applications
centralised
procedure

Applications
mutual
recognition

% Centralised

% Mutual
recognition

1

5

1

6

5

2

0

1

4

3

4

2

100 %

83 %

20 %

67 %

56 %

50 %

0 %

17 %

80 %

33 %

44 %

50 %

20

14

59 %

41 %

64

New active substance is any substance, which has not been part of an authorised veterinary medicinal
product in any of the Member States by 1st January 1995.

34