5. 11. 84 Official Journal of the European Communities No C 293/43 
dose range. However, in most cases it will be necessary to develop suitable cold 
analytical methods to separate and assay quantitatively the metabolites and/or the 
parent compound. 
(d) Interpretation of data 
The mathematical methods used (graphical representation, computer analysis, 
pharmacokinetic formulas) should be stated, including the confidence limits. 
(e) Presentation and evaluation of the results 
In summarizing data obtained from more than one subject, it is usually preferable 
to analyze individual data and at a later stage to average the pharmacokinetic con­
stants so obtained. 
Proper statistical analysis of the data obtained should be made and the inter- and 
intra-individual variations estimated, in at least some of the studies where the num­
ber of subjects is large enough. 
Proposal for a Council Directive amending Directive 65/65/EEC on the approximation 
of provisions laid down by law, regulation or administrative action relating to proprietary 
medicinal products 
COM(84) 437final 
(Submitted by the Commission to the Council on 3 October 1984) 
(84/C 293/05) 
THE COUNCIL OF THE EUROPEAN 
COMMUNITIES, 
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, 
Having regard to the opinion of the European Par­
liament, 
Having regard to the opinion of the Economic and 
Social Committee, 
Whereas point 8 of the second paragraph of 
Article 4 of Council Directive 65/65/EEC ('), as last 
amended by Directive 83/570/EEC (2) provides that 
various types of proof of the safety and efficacy of a 
proprietary medicinal product may be put forward 
in an application for marketing authorization 
depending upon the objective situation of the medi­
cinal product in question; 
Whereas experience has shown that it is advisable to 
stipulate more precisely the cases in which the results of pharmacological and toxicological tests or 
clinical trials do not have to be provided with a view 
to obtaining authorization for a medicinal product 
which is essentially similar to an authorized prod­
uct, while ensuring that innovative firms are not 
placed at a disadvantage; 
Whereas additional details were provided in respect 
of the application of the abovementioned provision 
by Council Directive 75/318/EEC of 20 May 1975 
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 proprietary medicinal products (3), as 
amended by Directive 83/570/EEC; 
Whereas, however, considerations of public policy 
are against the repetition of tests on animals or trials 
in man without pressing reasons; 
Whereas it is also advisable to make the packaging 
of certain medicinal products, particularly sought 
after by drug addicts, more commonplace by sup­
pressing the obligation to mark the outer packaging 
(') OJ No 22, 9. 2. 1965, p. 369/65. 
O OJ No L 332, 28. 11. 1983, p. 1. O OJ No L 147, 9. 6. 1975, p. 1. 
No C 293/44 Official Journal of the European Communities 5. 11.84 
and the container of medicines classified as narcot­
ics with a special sign, 
HAS ADOPTED THIS DIRECTIVE: 
Article 1 
Directive 65/65/EEC is hereby amended as follows: 
1. Point 8 of the second paragraph of Article 4 is 
hereby replaced by the following text: 
'8. Results of: 
— physico-chemical, biological or micro­
biological tests, 
— pharmacological and toxicological tests, 
— clinical trials. 
However, and without prejudice to the law 
relating to the protection of industrial and 
commercial property: 
(a) the applicant shall not be required to 
provide the results of pharmacological 
and toxicological tests or the results of 
clinical trials if he can demonstrate: 
(i) either that the proprietary product 
is essentially similar to a product 
authorized in the country con­
cerned by the application and that 
the person responsible for the mar­
keting of the original proprietary 
product has consented to the phar­
macological, toxicological or clini­
cal references contained in the file 
on the original proprietary medi­
cinal product being used for the 
purpose of examining the applica­
tion in question; 
(ii) or, by reference to the published 
scientific literature, that the constit­uent or constituents of the proprie­
tary product have a well-established 
medicinal use with recognized effi­
cacy and an acceptable level of 
safety; 
(iii) or that the proprietary product is 
essentially similar to a product 
which has been authorized for more 
than 10 years in the country con­
cerned by the application; 
however, where the proprietary product 
is intended for a different therapeutic 
use from that of the other medicinal 
products marketed or is to be adminis­
tered by different routes or in different 
doses, the results of appropriate phar­
macological and toxicological tests 
and/or of appropriate clinical trials 
must be provided. 
(b) in the case of a new proprietary product 
containing known constituents not hith­
erto used in combination for therapeu­
tic purposes, the results of pharmacol­
ogical and toxicological tests and of 
clinical trials relating to that combina­
tion must be provided, but it shall not 
be necessary to provide references relat­
ing to each individual constituent.' 
2. Article 16 is repealed. 
Article 2 
Member States shall take the measures necessary 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.