No C 293/4 Official Journal of the European Communities 5. 11. 84 
ANNEX 
LIST OF HIGH-TECHNOLOGY' MEDICINAL PRODUCTS 
A. Medicinal products developed by means of new biotechnological processes 
which make use of genetic recombination, hybridoma technology, aneuploid cell strains and 
enzyme bioreactors. 
For example: 
— new vaccines, particularly synthetic vaccines, 
— new antibiotics, 
— interferons, 
— immunotoxins, 
— hormones, particularly peptide hormones (human insulin; growth hormone), 
— monoclonal antibodies and DNA hybridization probes used in vivo, 
— enzymes such as urokinase, 
— blood proteins or substitutes thereof: alpha I, antitrypsin, human seralbumin, factor 
VIII, etc. 
B. Other high-technology medicinal products 
— Medicinal products administered by means of new delivery systems which constitute a 
major innovation: transcutaneous systems, encapsulation in liposomes or polymers, 
drug targeting systems, etc. 
— Medicinal products containing a new substance claimed to be of major therapeutic 
interest. 
— New medicinal products based on radioisotopes. 
— Medicinal products the manufacture of which is based upon an advanced technique 
such as two-dimensional electrophoresis under gravity or microgravity. 
Proposal for a Council Directive amending Directive 75/318/EEC 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 
COM(84) 437final 
(Submitted by the Commission to the Council on 3 October 1984) 
(84/C 293/02) 
THE COUNCIL OF THE EUROPEAN Having regard to the opinion of the Economic and 
COMMUNITIES, Social Committee; 
Having regard to the Treaty establishing the Euro­
pean Economic Community, and in particular 
Article 100 thereof; 
Having regard to the proposal from the Commis­
sion; Whereas the testing of proprietary medicinal prod­
ucts must regularly be adapted to scientific and 
Having regard to the opinion of the European Par- technical progress in order to ensure optimum pro-
liament; tection of public health in the Community; 
5. 11.84 Official Journal of the European Communities No C 293/5 
Whereas, in order to achieve such optimum protec­
tion of health, the resources allocated to pharma­
ceutical research must not be squandered on obso­
lete or repetitive tests resulting from divergences 
between the Member States in assessing the state of 
the art in science and technology; 
Whereas, for ethical reasons, it is necessary to 
replace existing methods as soon as scientific and 
technical advances so allow by methods involving 
as few laboratory animals as possible; 
Whereas it is therefore necessary to introduce a 
rapid procedure for adapting to technical progress 
the requirements regarding the testing of medicinal 
products listed in the Annex to Council Directive 
75/318/EECC), as amended by Directive 83/570/ 
EEC (2), whilst ensuring close cooperation between 
the Commission and the Member States within a 
'Committee for the Adaptation to Technical pro­
gress of the Directives on the Removal of Technical 
Barriers to Trade in the Proprietary Medicinal Prod­
ucts Sector'; 
Whereas the requirements relating to the testing of 
medicinal products must also be capable of rapid 
revision by the same procedure, having regard to the 
evolution of test methods and of good laboratory 
practices recognized by the Community or in inter­
national trade in medicinal products, 
HAS ADOPTED THIS DIRECTIVE: 
Article 1 
Directive 75/318/EEC is hereby amended as fol­
lows: 
1. The following Articles 2a, 2b and 2c are 
inserted: 
'Article 2a 
Any changes which are necessary in order to 
adapt the Annex to take account of technical 
progress shall be adopted in accordance with 
the procedure laid down in Article 2c. 
(') OJ No L 147, 9. 6. 1975, p. 1. 
Q OJ No L 332, 28. 11. 1983, p. 1. Article 2b 
1. A Committee on the Adaptation to Tech­
nical Progress of the Directives on the Removal 
of Technical Barriers to Trade in the Proprietary 
Medicinal Products Sector, hereinafter called 
"the Committee", is hereby set up; it shall con­
sist of representatives of the Member States 
with a representative of the Commission as 
chairman. 
2. The Committee shall adopt its own rules of 
procedure. 
Article 2c 
1. Where the procedure laid down in this 
Article is to be followed, matters shall be 
referred to the Committee by the chairman, 
either on his own initiative or at the request of 
the representative of a Member State. 
2. The representative of the Commission shall 
submit to the Committee a draft of the measures 
to be adopted. The Committee shall deliver its 
opinion on the draft within a time limit set by 
the chairman, having regard to the urgency of 
the matter. It shall act by a qualified majority, 
the votes of the Member States being weighted 
as provided in Article 148 (2) of the Treaty. The 
chairman shall not vote. 
3. (a) The Commission shall adopt the mea­
sures envisaged where they are in 
accordance with the opinion of the 
Committee. 
(b) Where the measures envisaged are not 
in accordance with the opinion of the 
Committee, or if no opinion is adopted, 
the Commission shall without delay 
propose to the Council the measures to 
be adopted. The Council shall act by a 
qualified majority. 
(c) If, within three months of the proposal 
being submitted to it, the Council has 
not acted, the proposed measures shall 
be adopted by the Commission.' 
2. Part 2 of the Annex, 'Toxicological and Pharma­
cological Tests' is hereby amended as follows: 
(a) The following paragraph is inserted after 
the introductory paragraph: 
'The Member States shall ensure that the 
safety tests are executed in conformity with 
the principles of good laboratory practice 
recognized by Community law in the field 
of tests on dangerous substances, or in the 
absence thereof, with those recommended 
No C 293/6 Official Journal of the European Communities 5. 11.84 
by the Organization for Economic Coopera­
tion and Development.' 
(b) In Chapter I (B) 'Toxicity', the text of para­
graph 1 is replaced by the following: 
' 1. Single dose toxicity 
An acute test infers a qualitative and quan­
titative study of the toxic reactions which 
may result from a single administration of 
the active substance or substances con­
tained in the proprietary medicinal product, 
in the proportions and physico-chemical 
state in which they are present in the actual 
product. 
The acute toxicity test must be carried out 
on two or more mammalian species of 
known strain unless a single species can be 
justified. At least two different routes of 
administration shall normally be used, one 
being identical with or similar to that pro­
posed for use in human beings and the 
other ensuring systemic absorption of the 
substance. 
This study will cover the signs observed, 
including local reactions. The period during 
which the test animals are observed shall be 
fixed by the investigator as being adequate 
to reveal tissue or organ damage or recov­
ery, usually for a period of 14 days but not 
less than seven days, but without exposing 
the animals to prolonged suffering. Animals 
dying during the observation period should 
be subject to autopsy as also should all ani­
mals surviving to the end of the observation 
period. Histopathological examination 
should be considered on any organ showing macroscopic changes at autopsy. The maxi­
mum amount of information should be 
obtained from the animals used in the 
study. The single dose toxicity tests should 
be conducted in such a way that signs of 
acute toxicity are revealed and the mode of 
death assessed as far as reasonably possible. 
In suitable species a quantitative evaluation 
of the approximate lethal dose and informa­
tion on the dose-effect relationship should 
be obtained, but a high level of precision is 
not required. 
These studies may give some indication of 
the likely effects of acute overdosage in 
man and may be useful for the design of 
toxicity studies requiring repeated dosing 
on the relevant animal species. 
In the case of active substances in combina­
tion, the study must be carried out in such a 
way as to check whether or not there is en­
hancement of toxicity or if novel toxic 
effects occur.' 
Article 2 
Member States shall take the measures necessary in 
order to comply with this Directive no later than 
1 January 1986. They shall forthwith inform the 
Commission thereof. 
Article 3 
This Directive is addressed to the Member States. 
Proposal for a Council Directive amending Directive 81/852/EEC on the approximation 
of the laws of the Member States relating to analytical, pharmaco-toxicological and 
clinical standards and protocols in respect of the testing of veterinary medicinal products 
COM(84) 437final 
(Submitted by the Commission to the Council on 3 October 1984) 
(84/C 293/03) 
THE COUNCIL OF THE EUROPEAN 
COMMUNITIES, Having regard to the proposal from the Commis­
sion; 
Having regard to the Treaty establishing the Euro­
pean Economic Community, and in particular 
Article 100 thereof; Having regard to the opinion of the European Par­
liament; 
Having regard to the opinion of the Economic and 
Social Committee;