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il COMMISSION OF THE EUROPEAN COMMUNITIES 
C0M(91) 39 final 
Brussels, 15 February 1991 
REPORT FROM THE COMMISSION TO THE COUNCIL 
ON THE ACTIVITIES OF 
THE COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS 
11 
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I. INTRODUCTION 
1. Objective of the report 
The Commission has recently presented its proposals for the future 
system for the free movement of medicinal products (both for human and 
veterinary use) within the Community^1), Including a substantial 
explanatory memorandum which provides the background to the Intro­
duction of the proposals. The objectives of the future system can best 
be met by a nuanced approach involving two authorization procedures-, 
one decentralised and the other centralized. These procedures have 
been elaborated from the experience gained with the current Community 
procedures, namely the 'multi-state' and 'concertation' procedures. 
This report is an opportunity to present the experience and results of 
the current procedures in respect of medicinal products for human use, 
against which the proposals for the future system may be considered. 
This document also reports, In accordance with the first paragraph of 
Article 15 of Council Directive 75/319/EEC^2^, on the operation of 
the procedure laid down In chapter 111 of that Directive ( i.e. multi-
state procedure) and its effects on the development of intra-Communlty 
trade, thus updating earlier reports^3). 
(1) C0M(90)283 of 14.11.1990 
(2) In order to facilitate reading of this report, texts of the Community 
pharmaceutical legislation cited are summarized In chronological order 
In Annex 1. 
(3) Reports from the Commission to the Council on the operation of the 
Committee for Proprietary Medicinal Products: 
C0M(79) 59 Of 22.2.1979; 
C0M(80) 149 Of 31.3.1980; 
C0M(81) 363 Of 13.7.1981; 
C0M(82) 787 of 3.12.1982; 
C0M(84) 437 of 3.12.1984, (explanatory memorandum); 
C0M(88) 143 of 22.3.1988. 
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The first Community procedure for the co-ordination of national 
actions on applications for marketing authorizations, which had been 
established by Directive 75/319/EEC, was extensively documented in the 
1988 report to the Council cited above. This earlier procedure ceased 
to function once the new 'multi-state' procedure came Into operation 
towards the end of 1986. However, given certain similarities between 
it and the multi-state, It Is illustrative to compare the experience 
gained with each procedure. 
Directive 87/22/EEC introduced on 1st July 1987 a further Community 
procedure, namely the 'concertation' procedure. This Community 
procedure differs fundamentally from the multi-state procedure in 
that, it is applicable prior to any national decisions concerning high 
technology medicines, particularly those produced by biotechnology. 
Although only in place for a few years, some illustration of its 
operation can already be given. 
2. Content of the report 
The present report of the Commission to the Council relates to the 
global activities of the Committee for Proprietary Medicinal Products 
and Its working parties, and Includes the operation of the two 
Community procedures (multi-state and concertation) for the co-ordi­
nation of national authorizations to place medicines for human use on 
the market, in accordance with Community legislation, as well as 
developments In the area of pharmacovlgllance and International 
harmonisât Ion. 
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in performing Its role as set out in Directive 75/319/EEC, the 
Committee for Proprietary Medicinal Products (CPMP) gives an opinion 
as to whether a particular medicinal product complies with the re­
quirements set out in Directive 65/65/EEC. Its activities are 
therefore not restricted to new applications for marketing authori­
zations, but also Include appropriate scientific and administrative 
requirements for the making of applications for marketing authorizat­
ions. Much of this work is accomplished by the CPMP through its 
working parties and expert groups, which provide an invaluable support 
to the Committee and to the Commission. 
The work of the CPMP does not end with the decision to grant or refuse 
a marketing authorization. The Committee maintains a watchful eye on 
the medicinal products on the market and is constantly active In 
monitoring the safety and efficacy of medicines on the market, and any 
change to the side effect profile of a medicinal product. This latter 
activity, known as pharmacovlgllance, has progressively expanded and 
a number of Innovative procedures have been adopted. 
On the basis of its expertise, the CPMP has also supported the 
Commission in international discussions on technical requirements for 
the authorization of medicinal products, the exchange of scientific 
knowledge and efforts towards International harmonisation of testing 
requirements for pharmaceutical products. 
In order to reflect the wide scope of activity of the Committee, all 
of these aspects are considered. 
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II. ACTIVITIES OF THE CPMP 
1. Membership of the Committee 
1.1 The Committee for Proprietary Medicinal Products, in accordance with 
Its Rules of Procedure (111/492/77), consists of one representative 
for each Member State and one representative of the Commission. One 
alternate Is appointed for each of the representatives. A list of the 
current membership of the CPMP is given in Annex 2. 
1.2 The Committee elects Its chairman from among Its members by absolute 
majority and secret ballot. The term of office of the chairman shall 
be three years, renewable once only. Until September 1988, 
Dr. Teljgeler, had served two successive terms. Professor 
D. Poggiolini was then elected and currently serves as chairman. 
1.3 Two deputy chairmen are appointed, one elected by the Committee and 
the other appointed by the Commission. In May 1989, Professor 
J.M. Alexandre was elected deputy chairman, while Mr. Fernand Sauer 
continues to serve as deputy chairman representing the Commission. 
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2. Communication and Information 
2.1 The work of the CPMP is of pivotal importance In the application of 
the Community pharmaceutical directives. Equally the views of the CPMP 
on a range of issues are of considerable interest and relevance to the 
pharmaceutical Industry. Given the volume of Information produced, the 
services of the Commission have brought together the relevant texts 
and published them in a series entitled 'Rules governing Medicinal 
Products In the European Commun Ity'(4). This series was first 
published In January 1989, and In keeping with the Committee's policy 
of openness, will be updated and expanded progressively. 
* Volume I of the series contains the binding texts adopted by the 
Community relating to medicinal products for human use. Catalogue 
number CB-55-89-706-EN-C. 
* Volume II is the Notice to Applicants, which replaced the version 
published In 1986. Catalogue number CB-55-89-293-EN-C. 
* Volume III contains technical guidelines dealing with quality in­
cluding biotechnology testing, pharmaco-toxIcologlcal and clinical 
studies. Catalogue number CB-55-89-843-EN-C. 
* Volume IV Is the guideline on Good Manufacturing Practice. Catalogue 
number CB-55-89-722-EN-C. 
There Is also a Volume V to the series which deals exclusively with 
veterinary medicinal products. 
(4) "Rules governing medicinal products in the European Community", 
available from the Office for Official Publications of the European 
Communities, 2 rue Mercier, L-2985 Luxembourg 
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2. Communication and Information 
2.1 The work of the CPMP is of pivotal importance in the application of 
the Community pharmaceutical directives. Equally the views of the CPMP 
on a range of issues are of considerable interest and relevance to the 
pharmaceutical industry. Given the volume of Information produced, the 
services of the Commission have brought together the relevant texts 
and published them in a series entitled 'Rules governing Medicinal 
Products in the European Commun Ity'(4>. This series was first 
published in January 1989, and in keeping with the Committee's policy 
of openness, will be updated and expanded progressively. 
* Volume I of the series contains the binding texts adopted by the 
Community relating to medicinal products for human use. Catalogue 
number CB-55-89-706-EN-C. 
* Volume II is the Notice to Applicants, which replaced the version 
published In 1986. Catalogue number CB-55-89-293-EN-C. 
* Volume III contains technical guidelines dealing with quality in­
cluding biotechnology testing, pharmaco-toxicological and clinical 
studies. Catalogue number CB-55-89-843-EN-C. 
* Volume IV is the guideline on Good Manufacturing Practice. Catalogue 
number CB-55-89-722-EN-C. 
There is also a Volume V to the series which deals exclusively with 
veterinary medicinal products. 
(4) "Rules governing medicinal products in the European Community", 
available from the Office for Official Publications of the European 
Communities, 2 rue Mercier, L-2985 Luxembourg 
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4. Harmonisation of scientific requirements 
4.1 Council Directive 75/318/EEC, as amended, sets out the laws relating 
to analytical, pharmaco-toxIcological and clinical standards and 
protocols in respect of the testing of medicinal products. Since its 
establishment, the CPMP has attached a high priority to the preparat­
ion of guidelines on the quality, safety and efficacy of medicinal 
products. 
4.2 These guidelines serve a two-fold objective. Firstly, they are Inten­
ded to provide a basis for a practical harmonisation of the manner in 
which the Member States interpret and apply the detailed requirements 
for the demonstration of quality, safety and efficacy contained In the 
Community directives. Secondly, they are intended to facilitate the 
preparation of applications for marketing authorization which are 
recognised as valid by all 12 Member States. 
4.3 The Rules governing Medicinal Products In the European Community, 
volume III (see 2.1 above) contains guidelines published up to January 
1989. A list of guidelines adopted and prepared since then is given in 
Annex 3 and will be published as an addendum to Volume III of the 
series 'Rules governing Medicinal Products in the European Community'. 
5. Working part les 
5.1 At an early stage in Its operation, the CPMP identified the need for 
specialist support In a range of scientific areas. Therefore a number 
of working parties were set up (Efficacy and Safety in 1977, Quality 
in 1985, Pharmacovlgllance and Operations In 1989). These working 
parties which are Intrinsically part of the CPMP, support the 
Committee In its role of giving scientific opinions on applications 
received through the Community procedures. 
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5.2 In parallel in 1985, the Commission set up a working party on biotech­
nology, with the Joint tasks of helping the Commission In the pre­
paration and technical requirements for the 'biotechnology' Directive 
(see Annex 1), and a second function which is of growing relevance, 
the preparation of discussions for CPMP opinions on applications for 
products derived from biotechnology. 
5.3 With the growing numbers and indeed complexity of applications, the 
working party structures have adapted by operating in a flexible, 
responsive and selective manner. This Involves the working parties 
working Jointly on identified problems; individual experts being 
convened In ad hoc expert meetings; or invited specialists Joining a 
working party for a specific discussion. A recent example was the 
special expert meeting on AIDS products held on 6.6.90. 
5.4 The facility of convening disparate experts, from diverse disciplines 
has become an integral part of the operation of the CPMP and its 
working parties, given the necessity to merge and blend expertise so 
as to obtain an overall assessment of benefit/risk. The success of 
this flexible structure, which will be further developed, means that 
the CPMP will be well placed to deal with the wide array of applicat­
ions and act as a bridge from today's activities Into the future 
system. 
5.5 This flexibility of the working party structure also permits a large 
number of European experts to feed into the system. Currently there 
are several hundreds of experts available for a CPMP opinion, and the 
lists of available experts nationally are continuously updated. The 
principle areas of scientific activity divide as follows: 
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* Efficacy: Guided by Its chairman, Prof. J.M. Alexandre, the Efficacy 
working party has considered both general issues and topics of 
specific therapeutic concern. A most important guideline which was 
finalized In July '90 was "Good Clinical Practice ( I Ii/3976/89)". 
Over the period 1988 to October '90, the working party met 8 times, 
with 4 drafting group meetings. Special experts were co-opted for 
guidelines on Anti-cancer medicinal products (from EORTC), Radio­
pharmaceuticals and Bioavailability. 
* Operations: As described above (paragraph 3.2 of this Chapter), this 
working party Is chaired by Dr. C. Teljgeler. 
* Pharmacovlgllance: With Prof. Royer as chairman, this recently 
established working party Is preparing harmonised approaches for the 
monitoring and collection of information on adverse drug reactions 
(ADR's). In addition to 11 meetings, the working party has liaised 
with the World Health Organisation on the international monitoring 
scheme. 
* Quality: With the stewardship of its chairman, Mr. A.C. Cartwrlght, 
the quality working party has been confronted with and has success­
fully resolved an Important number of difficult problems. The 
working party has collaborated with the Efficacy, Safety and 
Biotechnology working parties In turn on a range of guidelines and 
Identified problems. In the last two years there have been 11 full 
meetings of the working party, two drafting groups i.e. Radiopharma­
ceuticals (Dr. K. Krlstensen) and Herbal Remedies (Prof. Hefendehl); 
and 5 ad hoc groups. 
* Safety: Under the chairmanship of Prof. R. Bass, the safety working 
party has considered a diverse range of topics. In parallel with Its 
work on guidelines, the group has also considered the toxicology of 
a selection of substances. The working party met on 7 occasions, 
consulted outside experts on ImmmunotoxIcity and reproduction 
toxicity and convened 3 drafting groups for selected topics. 
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5.6 Moreover, with effect from 1st July 1987, the Council has delegated to 
the Commission the power to amend the Annex to Directive 75/318/EEC 
which contains the legal requirements for the conduct of analytical 
and pharmaco-toxIcologlcal tests and clinical trials. With the adopt­
ion of the 'Extension' Directives setting out additional provisions 
for immunological medicinal products consisting of vaccines, toxins or 
serums and allergens; radiopharmaceuticals; medicinal products derived 
from human blood or human plasma, It is necessary to modify the tech­
nical Annex to Directive 75/318/EEC relating to analytical, pharmaco-
tox Icologlcal and clinical standards and protocols in respect of the 
testing of medicinal products. 
The CPMP and Its working parties have assisted the Commission In 
preparing appropriate revisions, in order to take account of 
scientific progress. 9 ad hoc drafting groups on immunological 
products, vaccines in general and influenza vaccine in particular, 
comprising experts from diverse disciplines, have considered the 
appropriate revisions, which will be considered by the Committee on 
the Adaptation to technical progress of the Directives In 1991. 
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III. MULT I-STATE PROCEDURE 
1. Principles of the multi-state procedure 
1.1 The legal rules governing the multi-state procedure are set out in 
Chapter III of Directive 75/319/EEC, as amended by Directive 
83/570/EEC. A full explanation of the multi-state procedure Is given 
in the Notice to Applicants. 
1.2 The primary purpose of the multi-state procedure is to make It easier 
for a person who has already obtained a marketing authorization In one 
Member State to get further marketing authorizations for the product 
concerned in two or more of the other Member States. The reduction of 
the number of Member States concerned from five to two was one of the 
changes Introduced in the new procedure (effective 1.10.86). 
1.3 The basis upon which the multi-state procedure was established was 
that a medicinal product, manufactured and marketed In one Member 
State on the basis of harmonized provisions, should be allowed into 
another Member State, taking into due consideration the initial 
authorization, save In exceptional cases which would be submitted to 
the Committee for Proprietary Medicinal Products. On this account, 
only exceptional cases would be referred to the CPMP for opinion. 
1.4 On the basis of the same documentation, and taking the marketing 
authorization granted by the first Member State in due consideration, 
the authorities of the Member States to which an application Is 
addressed have 120 days to grant authorization to market the product 
In their country or to formulate reasoned objections. 
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1.5 Where one or more objections are advanced, the matter Is referred to 
the CPMP which considers the grounds for the objections and any 
written or oral explanations provided by the applicant, before Issuing 
Its opinion. 
1.6 This opinion, which Is not legally binding, Is addressed to the Member 
States and to the applicant. Within a period of 60 days from the date 
of the opinion, the Member States must decide on what action to take 
pursuant to the CPMP opinion and must Inform the CPMP of their 
decision. 
2. Operation of the multi-state procedure 
2.1 In order to examine the operation of the multi-state procedure, it is 
useful to Identify the key steps that punctuate the procedure (figures 
for each step are up to the end of October 1990). 
1st step: the applicant company notifies Its Intention to start a 
multi-state procedure 142 applications (of which 3 
applications were withdrawn as the applicant did not comply 
with the requirements of Article 9 of Directive 83/570/EEC, 
while 2 further applications were withdrawn due to detection 
of serious side-effects). 
2nd step: the concerned Member States confirm the receipt of a valid 
application and the period of 120 days in Article 9 of 
Directive 75/319/EEC Is Initiated by a telex from the 
Commission to the Member States...122 applications 
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3rd step: a Member State takes due consideration of the first 
authorization and authorises the medicinal product ....no 
application I i.e. 0% of applications 
raises reasoned objections within the 120 day period laid 
down by the Directive 122 applications I.e. 100% of 
applicatIons 
4th step: the CPMP gives an opinion on applications referred to It 
92 applIcatIons 
5th step: all concerned Member States notify the action they have 
taken on the basis of the opinion completed procedures 
i.e. for which all concerned Member States have notified 
their decision, 45 applications. 
2.2 Up to the end of 1990, the multi-state procedure has proven to be much 
more popular than the previous procedure at 142 applications In four 
years vs. 41 applications in eight years. 
The following chart Illustrates the number of multi-state procedures 
which have started each year (I.e. based on the start of the 120 day 
period), broken down by quarter: 
1986 1987 1988 1989 1990 
Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 
111 8676 568 11 7 10 13 9 776 
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2.3 These 142 procedures correspond to a total of 738 national applicat­
ions. Thus the average multi-state procedure concerns a little more 
than five ( 5.20) recipient countries. This is interesting as one of 
the Improvements requested and indeed implemented with the 
Introduction of the new multi-state procedure (Directive 83/570/EEC) 
was to reduce the threshold for entry to the procedure from a minimum 
of 5 countries to 2 countries. It might be suggested therefore that 
the benefit In reducing numbers was psychological rather than actual! 
Of these 142 applications 52% were for more than 5 Member States, 
whilst only 18% were for 2 Member States. The breakdown is as follows: 
Coverage (numbers) of countries by applications 
No. of countries concerned: 23456789 10 
No. of applications : 25 26 16 12 15 11 16 12 9 
2.4 The task of originally authorizing Member State in the multi-state 
procedure has fallen most heavily on two Member States i.e. United 
Kingdom and France. The preference for these original Member States 
was also evidenced in the previous procedure. 
Whilst all Member States are concerned in the multi-state procedure, 
Germany is by far the most frequent recipient. This may be due to the 
delays which currently exist with applications in Germany. 
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Former CPMP procedure (Directive 75/319/EEC) 1978-1986 
BE DK DE GR ES FR IR IT LX NL UK Total 
Country of origin 575--71---16 41 
Recipient country 33 26 25 12 - 15 24 28 37 35 18 253 
Multi-state procedure (Directive 83/570/EEC) 1986-October '90 
BE DK DE GR ES FR IR IT LX NL UK Total 
Country of origin 7 13 11 - - 34 14 9 - 11 43 142 
Recipient country 78 54 102 66 70 49 49 79 74 68 49 738 
2.5 In accordance with the terms of the Act of Accession, Portugal is not 
required to Implement Council Directives 65/65/EEC, 75/318/EEC, 
75/319/EEC, 78/25/EEC, 83/570/EEC, until 1 January 1991. 
However the Portuguese authorities have Indicated that they will 
accept national applications presented In accordance with the standard 
Community format (I.e. Notice to Applicants). 
3. Outcome of the procedure 
3.1 The actual experience of the multi-state procedure is not consistent 
with the spirit of the directive which Introduced It, since every 
single multi-state application has been referred for a CPMP opinion, 
even though the safeguard clause was only intended to be used In 
exceptional cases. 
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3.2 The degree to which Member States take into due consideration the 
first authorization can be seen from the frequency with which 
objections are raised. On a sliding scale, the concerned Member States 
may be rated. With such a grading, Luxembourg emerges as the Member 
State most consistently 'taking Into due consideration' the first 
authorisation i.e. in all cases the first authorisation has been 
accepted (unless the Committee opinion has subsequently been 
negative). At the other extreme, Italy has systematically raised 
reasoned objections In 93% of applications, whilst the Netherlands 
have raised objections in 92% of applications which they have 
received. 
BE DK DE GR ES FR IR IT LX NL UK 
Frequency of 
systematic 
objections 88 83 85 48 67 74 55 93 0 92 86 
raised, as a (%) 
3.3 On the initiative of the Chairman, the CPMP adopted a programme 
for Improving the efficiency of Its procedures In March 1989. As 
part of this programme, a number of innovations were introduced. 
a) in February '88, applicants were requested make available their 
single written response to objections raised 30 working days before 
the application would be considered by the CPMP. 
b) The CPMP introduced in April '88 an Informal meeting of rapporteurs 
of concerned Member States which considers the objections raised 
and the responses received, before the formal meeting of the CPMP. 
c) Since May '89, for all positive opinions, the CPMP attaches a 
summary of product characteristics (prepared In accordance with 
Article 4a of Directive 65/65/EEC). 
d) In November '89 the role of the "rapporteur" ( I 11/3479/89) in the 
multi-state procedure was clarified. 
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Arising from these improvements, and the regular exchanges between the 
Member States, the resolution of objections has been facilitated. 
However, the fundamental problem still remains, which is that 
objections are systematically made to every multi-state application 
and each application has to be discussed centrally in Brussels. 
Clearly the system was neither designed not resourced to cope with 
such a workload. 
3.4 The CPMP has given 92 opinions for multi-state applications up and 
including October '90. Of these 83 have been positive (on a simple 
majority basis). However this figure can only be taken as a guide as 
many of these opinions in fact contain a dissension from one or more 
Member States. 
Of the 92 opinions, 
* 61 have been unanimously positive (28 of 41 In former procedure), 
* 14 positive and 4 negative opinions have had a single dissenting 
Member State, 
* 3 positive and 3 negative opinions have had two dissenting Member 
States, 
* 3 positive opinions have had three dissenting Member States, 
* 2 positive opinions have had four dissenting Member States. 
3.5 In cases where a Member State dissents from the opinion of the CPMP, 
the reasons for their position are given In the opinion, as well as an 
Indication of what corrective action may be taken by the applicant. 
However, as the multi-state procedure does not provide for an appeal 
mechanism, once the opinion Is given, any further information supplied 
or any further appeal takes place nationally and in accordance with 
solely national provisions. Nevertheless, the CPMP follow closely the 
outcome of final decisions until all concerned Member States have 
properly notified the Committee. 
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3.6 The devolution of the resolution of outstanding problems back to 
national procedures has caused significant problems: 
Article 14.3 of Directive 75/319/EEC as amended, requires not I fat Ion 
by the Member States to the Committee of decisions on action arising 
from opinions of the CPMP. Unfortunately, delays considerably longer 
than the given 60 days have been evidenced. Some of the delay is of 
course caused by the failure of the applicant to supply the missing 
data in an efficient manner. An illustration of the extent of delays 
can be seen from the following: 
No. of months No. of Total no. of No. of countries 
since opinion procedures countries who have not finalised 
concerned a decision 
46 1 7 1 
39 1 8 1 
38 1 10 1 
35 2 10 3 
31 2 16 2 
27 2 15 2 
21 3 21 5 
18 1 10 4 
16 3 13 5 
14 1 6 1 
12 3 17 4 
10 2 14 4 
9 5 26 10 
7 2 12 4 
6 15 3 
Additionally, the resulting decisions, each taken in isolation of the 
other, Inevitably lead to different results and different authorizat­
ions in the Member States. 
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It is for this reason that the CPMP has focussed attention on the need 
to elaborate a guideline on the content of the summary of product cha­
racteristics, such that harmonised information may be made available 
throughout the Community. Work on this guideline Is progressing and a 
draft is anticipated early In 1991. 
4. HearIngs 
4.1 As part of the Improvements Introduced by the multi-state procedure, 
the opportunity for applicants to make written and oral explanations 
was established (Article 14 of Directive 83/570/EEC). Thus a company 
may present for an oral hearing in cases where one or more Member 
States have raised reasoned objections in the multi-state procedure, 
or In cases where one or more Member States have granted a marketing 
authorization while one or more Member States have refused It and the 
question has been referred to the CPMP. 
4.2 Of course, the concertation procedure also has a facility for hearings 
with applicant companies. In fact, informal discussions with expert 
working parties also occur for concertation applications. 
4.3 Companies may also be Invited to present for an oral hearing in 
pharmacovlgllance' cases (see Chapter IV). 
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4.4 Although there are no formal rules of procedure for the conduct of 
hearings, the CPMP recommends the following guidance: 
-The applicant should liaise with the Member State/rapporteur 
regarding the need for a hearing. The hearing should focus on those 
issues which have not been resolved In previous written submissions. 
-Without wishing to specify a formal time limit, the CPMP considers 
that hearings lasting more than half an hour will not usually be 
necessary, as a hearing is held to allow clarification of 
outstanding Issues by questioning from the members of the CPMP. 
- Any documents to be used In conjunction with a hearing should be 
distributed to the members of the CPMP 30 working days before the 
meeting. New studies/data cannot be fully taken Into account during 
such a short hearing, and therefore such data should be made 
available to the Member States at least 30 working days before the 
meeting. Very large volumes of new data may require a deferral of 
discussion In order to allow adequate time for consideration. 
- It would normally be appropriate for between one and four persons to 
appear on behalf of the company concerned. 
4.5 The facility for hearings has been In place since 1986. Since then the 
usage has been as follows: 
Multi-state procedure : 31 
Concertation procedure : 10 
Pharmacovlgllance : 3 
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4.6 It Is Important to appreciate that a hearing takes place in an 
environment that Is multi-lingual and that simultaneous technical 
Interpretation during the hearing is necessary. Equally, given the 
very heavy workload of the Committee, and the consequent necessity for 
short hearings, It Is not possible to resolve detailed and extensive 
technical points, and deficiencies In the dossier cannot be overcome 
through oral presentations. Therefore the value of the oral presentat­
ion should not be over-estimated. 
5. Evaluation of the multi-state procedure 
5.1 On the basis of the experience now gained, it is possible to draw some 
conclusions on the operation of the multi-state procedure: 
- The procedure is popular and attractive to industry, as evidenced by 
the number of applications received. 
- The eventual outcome of a procedure Is generally positive, which Is 
consistent with the underlying philosophy, bearing in mind that one 
Member State has already authorized the product. 
-The procedure achieves results, although not by the principle 
foreseen In the Directive, but rather through the systematic use of 
the provision set up for dealing with objections, and not by virtue 
of its normal principle for functioning i.e. mutual recognition. 
- The principle of mutual recognition as It underlines the multi-state 
procedure, has never worked. Many reasons have been put forward to 
explain this including national sovereignty and the need to apply a 
safeguard clause, administrative requirements In Individual Member 
States and the absence of a clear national legal basis for the 
devolution of responsibility to the first authorizing Member State. 
- 23 -
The multi-state procedure, although currently operating effectively, 
cannot continue to do so If each and every case is referred to the 
CPMP because due consideration Is not taken of the first authorisat­
ion. Given the volume Increase in the use of the procedure, the CPMP 
Itself has Identified necessary goals In its "Proposals for the 
Improvement of the current functioning of the CPMP" (111/3476/89): 
- A changed attitude to the multi-state procedure In order to obtain 
a consistent improvement in mutual recognition-, 
- Improvement of the technical role of the CPMP, especially Intended 
to render efficient the concertation procedure 
- Introduction of a binding European decision 
5.2 The Commission has taken account of the views of the Committee for 
Proprietary Medicinal Products In the preparation of its proposals for 
the future system of registration of medicinal products (mentioned 
above), particularly in relation to the necessity for the highest 
scientific standard needed for the assessment of applications for 
marketing authorisations and also the need for a binding European 
decision. 
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IV. CONCERTATION PROCEDURE 
1. Principles of the concertation procedure 
1.1 The legal rules governing the special Community procedure are set out 
In Council Directive 87/22/EEC. The objective of the special procedure 
Is to enable questions relating to the quality, safety and efficacy of 
medicinal products developed by means of new biotechnology processes 
and other high technology medicinal products to be resolved at 
Community level within the CPMP before any national decision is 
reached concerning a marketing authorization. 
1.2 The concertation procedure is obligatory for all medicinal products 
developed by means of the following biotechnological processes (List A 
of the Annex of Directive 87/22/EEC): 
- recombinant DNA technology 
-controlled expression of genes coding for biologically active 
proteins In prokaryots and eukaryots,Including transformed mammalian 
eel Is 
- hybrldoma and monoclonal antibody methods 
1.3 In addition, applicants for marketing authorization for the following 
groups of products may request that the application be considered 
under this procedure (List B of the Annex of Directive 87/22/EEC): 
- medicinal product developed by other biotechnological processes 
which constitute a significant Innovation; 
-medicinal product administered by means of new delivery systems 
which constitute a significant Innovation; 
-medicinal products containing a new substance or an entirely new 
indication which is of significant therapeutic interest; 
- 25 -
new medicinal products based on radio-isotopes which are of 
significant therapeutic Interest; 
medicinal products the manufacture of which employs processes which 
demonstrate a significant technical advance such as 2-dimentlonal 
electro-phoresis under micro-gravity. 
1.4 The timetable for the concertation procedure Is based on the require­
ment of Article 7 of Directive 65/65/EEC. Since the applications 
relate to complex processes which are deemed to be exceptional, the 
rapporteur, in establishing the period for review, systematically 
extends the time period of 120 days to include the additional 90 days 
provided for In exceptional cases by the directive. 
For variations however, the rapporteur is at liberty to reduce the 
period of review to less than 120 days, to as short a time as Is 
practical, given the nature of the variation. 
1.5 Given the very complex nature of the applications received In the 
concertation procedure, an expert working party, called the Biotech­
nology/Pharmacy working party, was established in 1986 to assist in 
the scientific evaluation of applications. 
This working party (see Chapter I, paragraph 5), whose chairman is 
Dr. G. Schild, has given technical advice to the CPMP in the many 
concertation applications which the CPMP has considered. 
2. Operation of the concertation procedure 
Since this directive came Into effect on 1st July '87, there have been 
applications In respect of 30 medicinal products. Of these 24 are for 
List A medicinal products, while 6 are for List B medicinal products. 
Of the 30 applications, the number of Member States concerned Is 337. 
In fact 25 applications concern all Member States except one. 
- 26 -
3. Choice of rappporteur 
3.1 Unlike the multi-state procedure, no Member State makes a decision 
regarding marketing authorization prior to the commencement of a 
concertation procedure. Therefore the applicant may Invite the Member 
State of its choice to act as rapporteur. 
3.2 The task of rapporteur Is better distributed between the Member States 
than in the multi-state procedure, as can be seen from the following 
(the 1/2 refers to an application where the UK and Fr acted as Joint 
rapporteurs). 
BE DK DE GR ES FR IR IT LX NL PO UK Total 
Country of origin 1 5 4 - - 4 1/2 1 2 - 4 - 8 1/2 30 
Recipient country 29 29 29 25 28 29 28 28 27 29 27 29 337 
3.3 The nationality of the applicants (by reference to their group 
headquarters) points up the degree of Innovation of the pharmaceutical 
industry. 15 of the applications were from pharmaceutical companies of 
the Community (De - 6; Dk - 4; UK - 3; It - 1; NI - 1), while 13 
applicants were from the United States, and one each from Sweden and 
Switzerland. 
- 27 -
4. Variations 
A medicinal product which has been considered under the concertation 
procedure, also avails of co-ordinated review of variations or ex­
tensions to the medicinal product. In July '89, the CPMP clarified the 
position with regard to variations and extensions. Variations always 
concern all Member States which have authorised the medicinal product. 
Given that the medicinal products considered under this procedure are 
innovatory by their nature, It is not surprising that a high number of 
variations and extensions are applied for each year. On the current 
database of medicinal products, the number of variations has been 16. 
Of these 16 variations, 9 opinions have been given, all of which have 
been positive. 
5. Outcome of the procedure 
5.1 Up to October '90, the CPMP has given 11 opinions under the 
concertation procedure. One opinion was given prior to the formal 
implementation of the Directive, to allow a 'test-run' of the 
procedure. 
5.2 Of the 11 opinions given, all have been positive. Whilst this may 
sound impressive, In fact, the practice is for applicants to withdraw 
an application when it becomes evident that a negative opinion would 
be given. This practice of withdrawing the application Is entirely 
consistent with a company's responsibility to patients, i.e. if a 
medicinal product does not meet the necessary standards of quality, 
safety and efficacy is should not be marketed. A total of two 
applications have been withdrawn to date. 
- 28 -
5.3 For the 11 opinions given for first applications, these represent 121 
national applications, for which 79 authorisations have been granted 
and 42 are awaiting national decision. If the 9 opinions on variations 
are added to this, the total number of national applications would 
rise to 217, of which 121 have received authorisations and 96 are 
awaiting national decision. 
A problem similar to that encountered with the multi-state procedure 
is also evident with the concertation procedure. This is the delay 
between the giving of an opinion by the Committee and the notification 
of a national decision on that opinion. By far the worst case is the 
application, for which two Member States are outstanding for four 
years on a decision on the CPMP opinion. An illustration of the extent 
of delays can be seen from the following: 
No. of months No. of Total no. of No. of countries 
since opinion procedures countries who have not notified 
concerned a decision 
27 1 12 1 
26 1 12 1 
24 1 1 1 
16 2 19 4 
12 1 11 5 
10 1 12 6 
7 1 12 3 
- 29 -
6. Products authorised as a result of the concertation procedure 
In accordance with Article 4.8.a) of Directive 65/65/EEC, an abridged 
application for a medicinal product essentially similar to a medicinal 
product of List A or List B, can be made after a period of ten years 
from the date of first authorisation in the Community. The following 
products have been considered under the concertation procedure and 
have received their first authorisation in the Community: 
1. ORTHOCLONE (0KT3); authorization holder Is CI lag; first 
authorized In France on 03.06.1986: 
2. NORD ITROP IN (recombinant Human growth hormone); authorization 
holder Is Nordlsk Gentofte; first authorized in Denmark on 
28.04.1988: 
3. INSULIN (recombinant Insulin); authorization holder is Novo 
Industrl A/S; first authorized In Italy on 06.07.1988: 
4. EPREX (erythropoeitIn); authorization holder Is CI lag; first 
authorized In France on 04.08.1988: 
5. M0N0CLATE P (Mab purified factor VIII); authorization holder Is 
Armour Pharmaceutical Company; first authorized In Italy on 
03.10.1989: 
6. PROLEUKIN (recombinant Interleukin); authorization holder is 
Eurocetus; first authorization In Spain on 23.06.1989: 
7. MY0SCINT (antimyosin Fab - DTPA); authorization holder is 
Centocor Europe; first authorization In Italy on 13.06.1989: 
- 30 -
8. ENGERIX - B (recombinant hepatitis B vaccine); authorization 
holder Is Smith Kline French Labo; first authorization in 
Belgium on 10.12.1986: 
9. REC0RM0N (erythropoeitIn); authorization holder is Boehringer/ 
Mannheim; first authorized in Denmark on 01.03.1990: 
10. GENOTROPIN (recombinant human growth hormone); authorization 
holder is KabI Blopharma; first authorization for 16 I.U. in 
Denmark on 19.02.1990: 
11. RETROVIR (zldoduvlne); authorization holder Is The Wellcome 
Foundation; first authorisation for asymptomatic patients In 
Denmark on 20.06.1990. 
- 31 -
V. PHARMACOVIGILANCE 
1. Continued safety monitoring 
1.1 During the period of marketing a medicinal product, It may be 
necessary, In order to safeguard public health, to take urgent 
measures such as the modification of the terms of marketing 
authorization, or Its even suspension. The general activity of 
monitoring the side-effects of a medicinal product, Including any 
active investigation of such incidence, may be Included within the 
meaning of pharmacovlgllance. 
1.2 Ever since Its establishment, the CPMP has exchanged Important 
Information (In accordance with Directive 75/319/EEC Articles 30 & 33) 
on matters of pharmacovlgllance. Internal procedures had been 
described in 1979 (111/1816/79) and 1982 (111/1917/82) Including a 
list of contact people for a system of rapid alert. 
1.3 Given the importance of this activity and the need for a most 
effective exchange of Information, particularly when public health Is 
at risk, the CPMP has recently developed further the procedures in 
this area. 
- 32 -
2. Drug mon i tor Ing/pharmacovI g 11ance 
2.1 In the Member States, different systems of pharmacovlgllance apply and 
consequently, information on medicinal products is collected In 
different ways. However, regardless of the method of collection used, 
be it spontaneous ADR reports, results of new studies, etc., the CPMP 
considered it essential that such Information, properly validated, be 
communicated as soon as possible to the competent authorities of the 
other Member States. Therefore a system of communication falling Into 
two parts, i.e. rapid alert and regular notification, was 
establI shed. 
2.2 In the Rapid Alert mechanism, the competent authority of the Member 
State of origin, i.e. the source of the information, Is responsible 
for sending out the Information to all other Member States and the 
Commission directly, with a copy to the CPMP secretariat. 
On the basis of experience with alert reports, an INFO FAX was adopted 
which a I lows: 
* the INN name ( as the main Identification); brand names, and company 
names although not necessarily the same In all Member States, are 
also be stated. 
* the fax includes sufficient details of the incident/report to allow 
all recipients to appreciate the significance of the report. 
* following a rapid alert communication, the competent authority of 
the Member State of origin prepares a background note for the next 
CPMP meeting. 
- 33 -
2.3 With Regular Communication, the exchange of pharmacovlgllance data 
takes place in the CPMP. Such exchange Is a fundamental responsibility 
of the Committee. However, given Its workload, the time of the 
Committee can be maximized by a preliminary screening of routine data. 
Equally Important Is the communication of data on defective batches of 
medicinal products, which may, In some cases, be of Interest to the 
pharmacovlgllance activity. The working party of the Pharmaceutical 
Inspectors have established a system for notification and rapid action 
In these circumstances. 
3. Screening of Information 
3.1 The growing Importance of pharmacovlgllance problems discussed by the 
CPMP, identified the need for a specialized group of experts dedicated 
to pharmacovlgllance, with a view to screening the large volume of 
information and providing technical preparation for the CPMP meeting, 
leading to the setting up of a pharmacovlgllance working party as 
mentioned in Chapter I, paragraph 5. 
This group was set up In February 1989, and a first report on 
pharmacovlgllance in the Member States was issued in September 1989 
(report on pharmacovlgllance 111/3577/89). 
3.2 The CPMP continues Its responsibility for pharmacovlgllance with on­
going procedures: 
* A DRUG INFORMATION monitor which identifies selected products and 
updates the Information on marketing authorization status and 
related changes; 
* Pharmacovlgllance HEARINGS with companies, eventually leading to 
pharmacovI g 11ance op In i ons; 
- 34 -
* The standardization of the SUMMARY OF PRODUCT CHARACTERISTICS for 
some products of Community interest for which adverse effects have 
been identified which require changes to the product particulars. 
4. Outcome of pharmacovlgllance activity 
4.1 In total, the CPMP has given 8 opinions on medicinal products arising 
from pharmacovlgllance reports, covering the following substances: 
Asp i r i n 
Lofepramine 
Suprofen 
Isotretinoin 
IsoxI cam 
F lunarIzlne 
FIecanIde/Enca i nI de 
GIafen i ne/Floctafen I ne 
4.2 A total of 8 rapid alerts have been exchanged In the last two years, 
using the INFO FAX mechanism. 
4.3 The Committee has considered the following products in Its programme 
of monitoring from 1988 to 1990: 
AdrIanomycIne, Arteparon, Ativan, Budesonlde, Carbosylan, Cronassial, 
Dlprlvan, Ex Ifone, Fenfluramine, Fenoterol, FIecanI de, F lunarizlne, 
Fluoxetine, Glafenlne/floctafenlne, Lldocalne, Propacetamol, PPSB, 
Prazosin, Phenothlazlne, Ibuprofen, Isotretinoin, IsoxI cam, 
Methaqualone, Metipranolol, Mianserin, Nitrendipine, Nitrofurazone/ 
Nitrofurantoin, Noscaplne, Retinol, Segontin, Slmvastatine, Sodium 
Aurothlomalate, Sulphamethoxazole, Sulphites, Terconazole, 
Thalidomide, Tlclopldlne, Trimethoprim, Tryptophan, Warfarin. 
- 35 -
VI. INTERNATIONAL TRADE AND OTHER ACTIVITIES 
1. International Harmonisation 
1.1 With the adoption and implementation of Community standards and texts 
in the pharmaceutical field, the acceptance of these standards and 
formats Internationally has grown. The Notice to Applicants format for 
the preparation of the dossier Is also accepted in the Nordic 
countries and by EFTA. The guideline on Good Manufacturing Practice 
has been accepted by the World Health Organisation. The guideline on 
stability testing is the first of its kind and caters for multiple 
climatic zones. Equally when embarking on more detailed activity, the 
CPMP first looks to internationally recognised methods and in general 
would adopt these If appropriate. For example, the WHO drug monitoring 
system. 
1.2 During 1989 therefore, both the Nordic Council and EFTA were invited 
to liaise with the technical working parties of the CPMP. In turn, 
Community experts are Invited to technical meetings of the Nordic 
Council and EFTA. Such exchange of technical expertise allows for the 
approximation of standards and the removal of technical barriers to 
trade. 
1.3 The convention relating to the elaboration of a European Pharmacopoeia 
was signed in 1964 within the framework of the Council of Europe. The 
European Community gave legislative force to the standards of the 
European Pharmacopoeia in Directive 75/318/EEC and In November 1989, a 
protocol for the accession of the EEC to the European Pharmacopoeia 
was opened for signature by participating States. The Protocol will 
enter into force after its ratification by all 19 states which are 
Parties to the Convention. 
- 36 -
1.4 In keeping with the general approximation of scientific standards, the 
Commission has established liaison with the United States Food and 
Drug Administration (FDA). Biannual meetings take place where 
exchanges of information facilitate understanding. The expertise of 
the CPMP has been fundamental in the preparation and successful 
outcome of these meetings. 
1.5 Following various missions by European experts and the Commission and 
in particular! the successful mission to Japan in September 1988, 
regular liaison with representatives of the Japanese Ministry of 
Health and Welfare (Koselcho) Is maintained. The appointment of a 
pharmaceutical expert to the Japanese delegation to the European 
Community in Brussels has greatly assisted the exchange of 
Informat ion. 
2. International Conference on Harmonisation 
2.1 Arising from the excellent relations which have developed, the 
Commission In association with the FDA and Koselcho authorities, have 
agreed to Jointly sponsor, with the international pharmaceutical 
Industry (IFPMA; EFPIA; US-PMA; JPMA), an International conference on 
the harmonisation of technical requirements for registration of 
pharmaceuticals for human use, to be held in Brussels in November 
1991. 
- 37 -
2.2 This conference has as objectives: 
- to provide a unique forum for dialogue between the main regulatory 
authorities and the pharmaceutical companies worldwide; 
- to identify the degree of pharmaceutical harmonisation already 
achieved bilaterally and the outstanding differences; 
- to agree on an action programme to complete International 
harmonisation (1991 - 1996) with a view to prevent unnecessary 
repetition of human and animal testing and to reduce pharmaceutical 
research and development costs. 
3. Intra-Communlty Trade 
3.1 From the previous reports (cited above) and from the many economic 
analyses (e.g. The Cost of Non-Europe in the Pharmaceutical industry, 
Volume 15; catalogue number CB -PP -88 -P14 -EN -C, available from the 
Office for Official Publications of the European Communities), 
approximately 67% of sales of medicinal products in the Community come 
from the Member States. This level has been relatively constant for 
the last decade. 
3.2 Figures for the geographic distribution of exports (for bulk and 
finished pharmaceuticals) are given in Annex 4, as well as the trade 
balance for pharmaceuticals for each of the Member States. 
- 38 -
3.3 Even though the numbers of multi-state and concertation procedures are 
growing, they only represent less than 10% of the total number of 
applications made In the Community each year. Therefore the Impact of 
the procedures on Intra-Communlty trade has not been possible to 
quantify, but may be assumed not to be substantial. However, what has 
been significant has been the progress of harmonisation which already 
has produced savings and reduced costs, e.g. a single format for 
applications, non-repetition of testing, the same requirements 
throughout the Community, it may equally be said that the procedures 
have facilitated Intra-Community trade and encouraged an appreciation 
of the resulting commercial opportunities, leading to an attitude of 
Community availability of medicinal products. 
- 39 -
LIST OF ANNEXES. 
Annex 1 List of major Community texts applying to 
medicinal products. 
Annex 2 Membership of the Committee for Proprietary 
Medicinal Products 
Annex 3 Status of CPMP guidelines 
Annex 4 Geographical distribution of exports of 
finished pharmaceuticals 
So 
Annex 1 
LIST OF MAJOR COMMUNITY TEXTS APPLYING TO MEDICINAL PRODUCTS 
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 (O.J. n° 22 of 9.2.65) 
COUNCIL DIRECTIVE 75/318/EEC of 20 May 1975 on the approximation of the 
laws of Member States relating to analytical, pharmacotoxIcologlcal and 
clinical standards and protocols In respect of the testing of proprietary 
medicinal products (O.J. n° L 147 of 9.6.75) 
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 
COUNCIL DECISION 75/320/EEC of 20 May 1975 setting up a Pharmaceutical 
Committee (O.J. n° L 147 of 9.6.75) 
COUNCIL DIRECTIVE 78/25/EEC of 12 December 1977 on the approximation of 
the laws of the Member States relating to the colouring matters which may 
be added to medicinal products (O.J. n° L 11 of 14.1.78) 
COUNCIL DIRECTIVE 81/851/EEC of 28 September 1981 on the approximation of 
the laws of the Member States relating to veterinary medicinal products 
(O.J. n° L 317 of 6.11.81) 
COUNCIL DIRECTIVE 81/852/EEC of 28 September 1981 on the approximation of 
the laws of the Member States relating to analytical, pharmaco-tox(co-
logical and clinical standards and protocols In respect of the testing of 
veterinary medicinal products (O.J. n° L 317 of 6.11.81) 
COMMISSION COMMUNICATION on parallel imports of proprietary medicinal 
products for which marketing authorizations have already been granted 
(O.J. n° C 115 of 6.5.82) 
COUNCIL DIRECTIVE 83/189/EEC of 28 March 1983 laying down a procedure for 
the provision of information In the field of technical standards and 
regulations (O.J. n° L 109 of 26.4.83) 
COUNCIL DIRECTIVE 83/570/EEC of 26 October 1983 amending Directives 
65/65/EEC, 75/318/EEC and 75/319/EEC on the approximation of provisions 
laid down by law, regulation or administrative action relating to 
proprietary medicinal products (O.J. n° L 332 of 28.11.83) 
COUNCIL RECOMMENDATION 83/571/EEC of 26 October 1983 concerning tests 
relating to the placing on the market of proprietary medicinal products 
(O.J. n° L 332 of 28.11.83) 
COMMISSION COMMUNICATION on the compatibility with Article 30 of the EEC 
Treaty of measures taken by Member States relating to price controls and 
reimbursement of medicinal products (O.J. n° C 310 of 4.12.86) 
- 2-
COUNCIL DIRECTIVE 86/609/EEC of 24 November 1986 on the approximation of 
laws, regulations and administrative provisions of the Member States 
regarding the protection of animals used for experimental and other 
scientific purposes (O.J. n° L 358 of 18.12.86) 
COUNCIL DIRECTIVE 87/18/EEC of 18 December 1986 on the harmonization of 
laws, regulations or administrative provisions relating to the 
application of the principles of good laboratory practice and the 
verification of their applications for tests on chemical substances (O.J. 
n° L 15 of 17.1.87) 
COUNCIL DIRECTIVE 87/19/EEC of 22 December 1986 amending Directive 
75/318/EEC on the approximation of the laws of the Member States relating 
to analytical, pharmaco-toxIcolog I cal and clinical standards and 
protocols in respect of the testing of proprietary medicinal products 
(O.J. n° L 15 of 17.1.87) 
COUNCIL DIRECTIVE 87/20/EEC of 22 December 1986 amending Directive 
81/852/EEC on the approximation of the laws of the Member States relating 
to analytical, pharmaco-toxIcolog lea I and clinical standards and 
protocols in respect of the testing of veterinary medicinal products 
(O.J. n° L 15 of 17.1.87) 
COUNCIL DIRECTIVE 87/21/EEC of 22 December 1986 amending Directive 
65/65/EEC on the approximation of provisions laid down by law, regulation 
or administrative action relating to proprietary medicinal products (O.J. 
n° L 15 of 17.1.87) 
COUNCIL DIRECTIVE 87/22/EEC of 22 December 1986 on the approximation of 
national measures relating to the placing on the market of high 
technology medicinal products, particularly those derived from 
biotechnology (O.J. n° L 15 of 17.1.87) 
COUNCIL RECOMMENDATION 87/176/EEC of 9 February 1987 concerning tests 
relating to the placing on the market of proprietary medicinal products 
(O.J. n° L 73 of 16.3.87) 
COUNCIL DIRECTIVE 88/182/EEC of 22 March 1988 amending Directive 
83/189/EEC laying down a procedure for the provision of information In 
the field of technical standards and regulations (O.J. n° L 81 of 
26.3.88) 
COUNCIL DIRECTIVE 88/320/EEC of 9 June 1988 on the Inspection and 
verification of Good Laboratory Practice (GLP) (O.J. n° L 145 of 11.6.88) 
COUNCIL DIRECTIVE 89/105/EEC of 21 December 1988 relating to the 
transparency of measures regulating the pricing of medicinal products for 
human use and their inclusion within the scope of national health 
Insurance systems (O.J. n° L 40 of 11.2.89) 
COUNCIL DIRECTIVE 89/341/EEC of 3 May 1989 amending Directives 65/65/EEC, 
75/318/EEC and 75/319/EEC on the approximation of provisions laid down by 
law, regulation or administrative action relating to proprietary 
medicinal products M1 
M* 
COUNCIL DIRECTIVE 89/342/EEC of 3 May 1989 extending the scope of 
Directives 65/65/EEC and 75/319/EEC and laying down additional provisions 
for Immunological medicinal products consisting of vaccines, toxins or 
serums and allergens 
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 
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, regulations or administrative action relating to 
proprietary medicinal products and laying down special provisions for 
medicinal products derived from human blood or human plasma 
COUNCIL DIRECTIVE 90/18/EEC of 18 December 1989 adapting to technical 
progress the Annex to Council Directive 88/320/EEC on the inspect ion and 
verification of Good Laboratory Practice (GLP) 
COUNCIL REGULATION (EEC)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 
COUNCIL DIRECTIVE .../.../EEC of 13 December 1990 amending Directive 
81/851/EEC on the approximation of the laws of the Member States relating 
to veterinary medicinal products 
COUNCIL DIRECTIVE .../.../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 
- 1 -
Annex 2 
COMITE DES SPECIALITES PHARMACEUTIQUES 
COMMITTEE FOR PROPRIETARTY MEDICINAL PRODUCTS 
Président / Chairman : 
Professore Dulllo POGGIOLINI Direttore Générale del Servizio FarmaceutIco, 
Mlnlstero délia Sanltà 
Vlale délia Civiltà Romana 7 
1-00144 Roma EUR 
Tel.: (39)(6) 592.58.63 
Tel ex: 625205 MlNSAN I 
Telefax: (39)(6) 592.58.24 
VIce-Prés Idents / 
Deputy Chairmen : 
M. le Professeur Jean-Michel ALEXANDRE Président de la Commission 
d'enregistrement des médicaments 
Ministère de la Solidarité, de la Santé et de 
la Protection sociale 
Direction de la Pharmacie et du Médicament 
1, Place de Fontenoy 
F-75700 Paris 
Tel.: (33)(1) 40.56.47.09 
Telefax: (33)(1) 40.56.53.55 
M. Fernand SAUER Chef d'Unité "Produits pharmaceutiques" 
Commission des Communautés européennes 
Direction générale du Marché intérieur et des 
Affaires Industrielles 
111/C-3 
Tel.: (322) 235.51.80 
Secrétariat du Comité des spécialités pharmaceutiques / 
Secretariat of the Committee for Proprietary Medicinal Products : 
Mrs. Marie C. DONNELLY 
Téléphone : (322) - 236.03.32 
- 235.69.35 
Commission des Communautés européennes 
Direction générale du Marché Intérieur et des 
Affaires industrielles 
Unité "Produits pharmaceutiques" 
D.G. Ill C 3 - NERV 2/8 
Rue de la Loi 200 
B-1049 BRUXELLES 
Telefax : 236.15.20 
236.28.93 
Telex : 21.877 COMEU B H5 
- 2 -HH 
LISTE DES MEMBRES / LIST OF MEMBERS 
a) Représentants / Représentatives : 
b) Suppléants / Deputies : 
BELGIQUE 
a) Mme. Nicole ROLAND 
b) Mlle. Christine BAETENS 
DANMARK 
a) Mr. Henning HOVGAARD 
b) Mrs. Agnete KJ/ERVIG 
DEUTSCHLAND 
a) Prof. Dr. Alfred G. HILDEBRANDT 
b) Prof. Dr. Jôrg SCHUSTER Pharmacien-Inspecteur, Chef de Service, 
Inspection générale de la Santé publique, 
Cité Administrât ive 
Quart 1er Vésale 
B-1010 Bruxelles 
Tel.: (32)(2) 210.49.18 
Telex: 25.768.MVGSPF B 
Telefax: (32)(2) 210.48.80 
PharmacI en-1nspecteur 
Inspection générale de la Pharmacie 
(idem) 
Tel.: (32)(2) 210.49.01 
Reglstreringschef, cand. pharm. 
SundhedsstyreI sen, Legem i ddeIafde Ii ng 
FrederIkssundsveJ 378 
DK-2700 BrdnshtfJ 
Tel.: (45) 42-94.36.77 
Telex: 35333 IPHARM DK 
Telefax: (45) 42-94.02.37 
AfdelIngsforstander cand. pharm. 
SundhedsstyreI sen (i dem) 
Tel.: (45) 42-94.36.77 
Leiter des Instituts fiir Arzneimittel des 
Bundesgesundhe i tsamtes 
SeestraBe 10 
D-1000 BerlIn 65 
Tel.: (49M30) 45.02.0 / 450.22.03 
Telex: (2627)(17) 308062 BGESA D 
Telefax: (49)(30) 450.22.07 
Dlrektor und Professor, Facharzt fiir 
Pharmakologie, Zuiassungskoordinator im 
Institut fur Arzneimittel des 
Bundesgesundhe!tsamtes (idem) 
Tel.: (49)(30) 450.22.88 / 450.23.10 
(Dr. Rembert Elbers - tel. 49 30 450.24.49) 
ESPANA / SPAIN - 3 -
HJ* 
a) Dr. F. GARCIA ALONSO Dlrecclon General de Farmacla y Productos 
Sanitarlos, Ministerlo de Sanidad y 
Consumo 
Paseo del Prado, 18 - 20 
E-28014 Madrid 
Tel.: (34)(1) 420.20.68 
Telex: 22.608 MSASS 
Telefax: (34)(1) 420.32.17 
b) Dra. Dolores SANDOVAL Centro Nacional 
Majadahonda 
28220 Madrid de Farmacobiologta 
FRANCE Tel.: (34)(1) 638.51.55 
Fax: (34)(1) 638.06.13 
a) M. le Professeur Jean-Michel ALEXANDRE Président de la Commission 
d'enregistrement des médicaments 
Ministère de la Solidarité, de la Santé et 
de la Protection sociale 
Direction de la Pharmacie et du Médicament 
1, Place de Fontenoy 
F-75700 Paris 
Tel.: (33)(1) 40.56.47.09 
Telefax: (33)(1) 40.56.53.55 
b) Mme. Campion Direction de la Pharmacie et du 
Médicament, Ministère de la Solidarité, de 
la Santé et de la Protection sociale 
Tel.: (33) (1) 40.56.51.13 
GREECE 
a) Professor D. VARONOS Chairman Registration Committee 
E.O.F. 
Voulis St. 4 
Athens 10562 
Tel .: (30)(1) 322.57.81 
resp. (30)(1) 779.08.41 (E.O.F.) 
(University) 
Telefax: (30)(1) 323.86.81 
b) Mme. J. YOTAKI Pharmacist, Head of Office 
Registration Division, E.O.F. 
(idem) 
Tel.: (30)(1) 323.09.11 
IRELAND 
ITALIA 
LUXEMBOURG - 4 - W6 
a) Dr. Alene SCOTT Medical Director 
National Drugs Advisory Board 
Charles Lucas House 
63-64 Adelaide Road 
Dub I In 2 
Tel.: (353)(1) 76.49.71 - 7 
Telex: 90542 NDAB El 
Telefax: (353)(1) 76.78.36 
b) Dr. Marie BURNS Deputy Medical Director 
National Drugs Advisory Board (idem) 
Tel .: (353M1) 76.49.71 - 7 
a) Dott. Romano CAPASSO Consigliere Ministeriale 
DIrezione Générale Servizio Farmaceutico 
Ministero del la Sanltà 
Vlale delta CIv11ta Romana 7 
1-00144 Roma EUR 
Tel.: (39)(6) 592.58.28 
Telefax: (39)(6) 592.58.24 
b) Dr. Marisa PAPALUCA Medical Assessor 
DIrezione Generate Servizio Farmaceutico 
Ministero delta Sanltà 
Vlale delta Civil ta Romana 7 
1-00144 Roma EUR 
Tel.: (39)(6) 592.58.26 
a) Mme. Jacqueline GENOUX-HAMES Pharmacien-Inspecteur, Direction de la 
Santé 
Division de la Pharmacie et des 
Médicaments 
10, rue CM. Spoo 
L-2546 Luxembourg 
Tel.: (352) 4.08.01 
Telex: 2546 SANTE LU 
Telefax: (352) 48.49.03 
b) M. Marc WIRTOR Pharmac i en-1nspecteur 
Division de la Pharmacie et des 
Médicaments (Idem) 
- 5 -W3 
NEDERLAND 
a) Dr. C.A. TEIJGELER Voorzltter College ter beoordeiing van 
geneesmlddelen, Ministerie van Welzijn, 
Volksgezondheld en Cultuur 
Postbus 5811 
NL-2280 HV Rljswljk (ZH) 
Tel.: (31)(70) 340.79.11 
Telex: 31680 WVC RW NL 
Telefax: (31)(70) 340.51.55 
b) Dr. W.F. VAN DER GIESEN Secretaris van het College ter beoordeiing 
van geneesmlddelen (idem) 
Tel.: (31M70) 340.72.10 
Telex and Telefax as above 
PORTUGAL 
a) Dr. J.A. ARANDA da SILVA Directeur général des Affaires 
Pharmaceut iques 
Ministère de la Santé 
Av. Estados Uni dos da America, 37 
1700 Llsboa / Portugal 
Tel.: (351)(1) 80.41.31 
Telex: 15655 MAS P 
Telefax: (351)(1) 84.80.331 
b) Mme. Marilia GRACA D'OLIVE IRA Chef de la Division du Médicament 
Ministère de la Santé 
Direction Générale des Affaires 
PharmaceutIques 
Av. Columbano Bordalo Plnhelro 87, 
1000 Llsboa / Portugal 
UNITED KINGDOM 
a) Dr. Keith H. JONES Director Medicines Control Agency 
Department of Health 
Medicines Control Agency 
Market Towers, 1 Nine Elms Lane 
London SW8 5NQ 
Tel.: (44)(71) 720.21.88, ext. 2188 
Telex: 883669 DHSSHQ G 
Telefax: (44)(71) 720.56.47 
b) Dr. David JEFFERYS Head, New Drugs and European Licensing 
Department of Health 
Medicines Control Agency (idem) 
Tel.: (44)(71) 720.21.88 
Annex 3 
STATUS OF CPMP GUIDELINES HI 
I. GUIDELINES ADOPTED BY THE CPMP UP TO DECEMBER 1988: 
PUBLISHED IN VOLUME I I I OF THE SERIES "RULES GOVERNING MEDICINAL PRODUCTS IN THE EUROPEAN 
COMMUNITY" (CATALOGUE NUMBER: CB-55-89-843-EN-C) 
2. GUIDELINES ADOPTED FROM DECEMBER 1988 TO JULY 1990: 
PUBLISHED (ADDENDUM VOLUME III, CATALOGUE NUMBER: CB-59-90-936-EN-C) 
3. GUIDELINES ADOPTED BY THE CPMP 
NUMBER I LANGUAGE TITLE DATE OF ADOPTION 
Local tolerance testing of medicinal I II/3979/89 EN-FR-DE December 1990 
Radiopharmaceuticals I III/3936/89 I EN-FR I December 1990 
4. GUIDELINES RELEASED BY THE CPMP FOR CONSULTATION 
TITLE 
Radiopharmaceuticals based on 
monoclonal antibodies of human 
or igin 
Validation of virus removal and 
inactivation procedures 
Recommendations for the development 
of non clinical testing strategies 
Categorisation of medicinal products 
for use in pregnancy 
Investigation of bioavailability and 
bioequivalence 
Specifications and control tests on 
the finished product 
Ethylene oxide 
Clinical Investigation of hypnotic 
medicinal products NUMBER 
LANGUAGE 
I II/3487/89 
Draft n° 5 
EN 
I I 1/8115/89 
Draft n° 6 
EN-FR 
I II/58/89 
Draft n° 7 
EN 
111/3862/89 
Draft n° 5 
EN 
111/54/89 
Draft n° 8 
EN 
111/3324/89 
Draft n° 7 
EN-FR 
111/9261/90 
Draft n° 1 
EN 
I II/3855/89 
Draft n° 3 
EN DATE OF 
RELEASE 
Feb. 1990 
March 1990 
July 90 
July 90 
July 90 
Dec. 90 
Dec. 90 
Dec. 90 DEADLINE FOR 
COMMENTS 
01.09.1990 
01.10.1990 
15.01.1991 
15.01.1990 
15.01.1990 
01.06.1991 
31.03.1991 
01.06.1991 FINALIZATION 
Ad Hoc Group 
March 1991 
CPMP May 1991 
Biotech Jan. 91 
CPMP Feb. 91 
CPMP May 1991 
CPMP May 1991 
CPMP March 1991 
Disc, in W.P. 
July 1991 
Disc. In W.P. 
Apr I I 1991 
Disc. In W.P. 
July 1991 
Annex 4 
GEOGRAPHICAL DISTRIBUTION 
OF EXPORT S 
FINISHED PHARMACEUTICALS 
•To 
EXPORTS 1988 
(mecus) GEOGRAPHICAL DISTRIBUTION OF EXPORTS 1988. 
BULK PHARMACEUTICALS. 
(Vitamins.Hormones.Vegetable Alkaloids.Antibiotics) 
TOTAL INTRA EXTRA CLASS 1 EFTA USA JAPAN CLASS2 EAST.EUR 
FR GERMANY 
FRANCE 
ITALY 739 
325 
513 38% 
46% 
33% 62% 
54% 
67% 35% 
34% 
44% 8% 
21% 
15% 17% 
4% 
15% 3% 
5% 
10% 20% 
18% 
16% 3% 
1% 
2% 
BELG.-LUXBG 89 85% 15% 8% 4% 1% 1% 6% 0% 
UTD. KINGDO 376 42% 58% 39% 6% 13% 13% 17% 1%' 
IRELAND 118 71% 29% 25% 9% 3% 11% 3% 1% 
DENMARK 
GREECE 
SPAIN 118 
8 
182 48% 
31% 
23% 52% 
69% 
77% 37% 
23% 
32% 11% 
8% 
13% 11% 
7% 
6% 0% 
7% 
9% 11% 
41% 
32% 4% 
2% 
4% 
PORTUGAL 145 57% 43% 22% 3% 12% 3% 18% 3% 
NETHERLANDS 66 95% 5% 3% 0% 1% 0% 2% 1% 
EUR 12 2.680 44% 56% 34% 11% 12% 6% 17% 2% 
EXPORTS 1988 
(mecus) FINISHED PHARMACEUTICALS 
(CN 30) 
TOTAL INTRA EXTRA CLASS 1 EFTA USA JAPAN CLASS2 EAST.EUR 
FR GERMANY 
FRANCE 
ITALY 3.040 
1 .865 
585 39% 
42% 
52% 61% 
58% 
48% 45% 
12% 
19% 20% 
6% 
6% 3% 
2% 
8% 16% 
2% 
1% 13% 
4 5% 
26% 2% 
1% 
2% 
BELG.-LUXBG 914 58% 42% 21% 13% 1% 2% 19% 2% 
UTD. KINGDO 2,156 41% 59% 31% 9% 9% 4% 27% 1% 
IRELAND 354 64% 36% 30% 4% 16% 4% 7% 0% 
DENMARK 
GREECE 
SPAIN 596 
46 
362 39% 
58% 
47% 61% 
42% 
53% 45% 
5% 
6% 25% 
0% 
4% 8% 
0% 
0% 9% 
0% 
0% 14% 
35% 
45% 2% 
0% 
0% 
PORTUGAL 31 30% 70% 14% 9% 4% 0% 56% 0% 
NETHERLANDS 777 51% 49% 31% 18% 2% 3% 16% 1% 
EUR 12 10.725 44% 56% 30% 13% 5% 7% 24% 1% 
Source :Eurostat. 
TRADE IN PHARMACEUTICALS 1988 S1 
GERMANY 
FRANCE 
ITALY 
BELG.-LUXBG 
UTD. KINGDO 
IRELAND 
DENMARK 
GREECE 
SPAIN 
PORTUGAL 
NETHERLANDS 
EUR 12 
Source:Eurostat FINISHED 
PHARMACEUTICALS 
(mecus) 
IMPORTS EXPORTS BALANCE 
1.623 3.040 1.416 
684 1.865 1.181 
1.058 585 -473 
734 920 186 
1.094 2.156 1,061 
213 354 141 
280 
128 
295 596 
47 
362 316 
-81 
67 
126 31 -96 
763 786 23 
6.998 10,741 3.743 BULK 
PHARMACEUTICALS 
(mecus) 
IMPORTS EXPORTS BALANCE 
482 
667 
613 
141 
•220 
55 
86 
45 
233 
49 
130 863 
325 
514 
90 
376 
118 
129 
0 
189 
37 
219 
862 381 
-341 
-98 
-51 
157 
64 
43 
-45 
-44 
-12 
89 
142 
(Thousand) 
B UK Ik UK tiR E P NL 
Ifinished lingredients 
BALANCE (Million of ECUS) 

ISSN 0254-1475 
COM(91) 39 final 
DOCUMENTS 
EN 05 
Catalogue number : CB-CO-91-067-EN-C 
ISBN 92-77-69427-0 
PRICE 1 • 30 pages: 3.50 ECU per additional 10 pages: 125 ECU 
Office for Official Publications of the European Communities 
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