Commission Directive 1999/83/EC of 8 September 1999 amending the Annex to Council Directive 75/318/EEC on the approximation of the laws of the Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products (Text with EEA relevance)
Date: 1999-09-08
Institutions: European Commission
Subjects: animal disease, approximation of laws, marketing, national implementing measure, pharmaceutical product, public health

15. 9. 1999

EN

Official Journal of the European Communities

L 243/9

COMMISSION DIRECTIVE 1999/83/EC

of 8 September 1999

amending the Annex to Council Directive 75/318/EEC on the approximation of the laws of the
Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in
respect of the testing of medicinal products

(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

meaning of ‘well established use’ pursuant to point 8(a)
and (b) of Article 4(2), of Directive 65/65/EEC;

Having regard to the Treaty establishing the European
Community,

Having regard to Council Directive 75/318/EEC of 20 May
1975 on the approximation of the laws of the Member States
and clinical
relating to analytical, pharmacotoxicological
standards and protocols in respect of the testing of medicinal
products (1), as last amended by Directive 93/39/EEC (2), and in
particular Article 2(a)(1) thereof;

(1) Whereas it is possible to replace results of pharmacolo-
gical and toxicological tests or clinical trials by detailed
references to published scientific literature if it can be
the constituent(s) of a medicinal
demonstrated that
product have a well-established medicinal use, with
recognised efficacy and an acceptable level of safety in
accordance with point 8(a) and (b) of Article 4(2), of
Council Directive 65/65/EEC of 26 January 1965 on the
approximation of provisions laid down by law, regula-
tion or administrative action relating to medicinal prod-
ucts (3);

(2) Whereas Article 1(2) of Directive 75/318/EEC provides
that where pursuant to point 8(a) and (b) of Article 4(2),
of Directive 65/65/EEC references to published data are
submitted (bibliographical applications), the provisions
of Directive 75/318/EEC shall apply ‘in like manner’;

(3) Whereas the increased speed of innovation and publica-
tion of innovation as well as the increasingly stringent
requirements foreseen by Community pharmaceutical
legislation for new medicinal products make it necessary
to define the conditions applicable to bibliographic
applications more closely and to determine more exactly
the meaning of
in Article 1(2) of
Directive 75/318/EEC;

‘in like manner’

(4) Whereas it must be ensured that

the possibility of
submitting
not
does
discourage innovative companies to publish results of
their research as quickly as possible;

‘bibliographical

applications’

(5) Whereas it is therefore necessary to lay down a more
detailed common understanding of the conditions for
the
‘bibliographical

and in particular

applications’

(1) OJ L 147, 9.6.1975, p. 1.
(2) OJ L 214, 24.8.1993, p. 22.
(3) OJ 22 of 9.2.1965, p. 369/65.

(6) Whereas it

is in particular necessary to clarify that
‘bibliographic reference’ to other sources of evidence
(postmarketing studies, epidemiological studies, studies
conducted with similar products, etc.) and not just tests
and trials may serve as a valid proof of safety and
efficacy of a product if an applicant explains and justifies
the use of these sources of information satisfactorily;

(7) Whereas the rules laid down in this Directive are to a
large extent in line with current administrative practice
in the majority of Member States;

(8) Whereas this amendment may help in solving practical
problems Member States are facing concerning the
authorisation of old medicinal products;

(9) Whereas the measures provided for in this Directive are
the Standing

in conformity with the opinion of
Committee for Medicinal Products for Human Use,

HAS ADOPTED THIS DIRECTIVE:

Article 1

The Annex to Directive 75/318/EEC is hereby amended as
shown in the Annex.

Article 2

1. Member States shall bring into force the laws, regulations
and administrative provisions necessary to comply with this
Directive no later than 1 March 2000.

2. When the Member States adopt the provisions set out in
paragraph 1, they shall contain a reference to this Directive or
shall be accompanied by such reference at the time of their
official publication. The procedure for such reference shall be
adopted by the Member States.

3.
The Member States shall communicate to the Commis-
sion the provisions of national law which they adopt in the
field covered by this Directive.

L 243/10

EN

Official Journal of the European Communities

15. 9. 1999

This Directive shall enter into force on the third day following its publication in the Official
Journal of the European Communities.

Article 3

This Directive is addressed to the Member States.

Article 4

Done at Brussels, 8 September 1999.

For the Commission

Karel VAN MIERT

Member of the Commission

15. 9. 1999

EN

Official Journal of the European Communities

L 243/11

1. In Part 3 of the Annex to Directive 75/318/EEC a new Section I is inserted.

‘I. Well-established medicinal use

ANNEX

For the purpose of demonstrating, pursuant to Article 4(8)(a)(ii) of Directive 65/65/EEC, that the constituent(s) of a
medicinal product have a well established use, with an acceptable level of safety, the following specific rules shall
apply:

(a) Factors which have to be taken into account in order to establish a “well established medicinal use” of
constituents of medicinal products are the time over which a substance has been used, quantitative aspects of
the use of the substance, the degree of scientific interest in the use of the substance (reflected in the published
scientific literature) and the coherence of scientific assessments. Therefore different periods of time may be
necessary for establishing “well established use” of different substances. In any case, however, the period of time
required for establishing a “well established medicinal use” of a constituent of a medicinal product must not be
less than one decade from the first systematic and documented use of that substance as a medicinal product in
the EU.

(b) The documentation submitted by the applicant should cover all aspects of the safety assessment and must
include or refer to a review of the relevant literature, taking into account pre- and postmarketing studies and
published scientific literature concerning experience in the form of epidemiological studies and in particular of
comparative epidemiological studies. All documentation, both favourable and unfavourable, should be com-
municated.

(c) Particular attention must be paid to any missing information and justification must be given why demonstration

of an acceptable level of safety can be supported although some studies are lacking.

(d) The Expert report must explain the relevance of any data submitted which concern a product different from the
product intended for marketing. A judgement must be made whether the product studied can be considered as
similar to the product which will be granted a marketing authorisation in spite of the existing differences.

(e) Post-marketing experience with other products containing the same constituents is of particular importance and

applicants should put a special emphasis on this issue.’

2. In Part 4 of the Annex to Directive 75/318/EEC a new section I is inserted:

‘I. Well established medicinal use

For the purpose of demonstrating, pursuant to Article 4(8)(a)(ii) of Directive 65/65/EEC, that the constituent(s) of a
medicinal product have a well established use, with recognised efficacy, the following specific rules shall apply:

(a) Factors which have to be taken into account in order to establish a “well established medicinal use” of
constituents of medicinal products are the time over which a substance has been used, quantitative aspects of
the use of the substance, the degree of scientific interest in the use of the substance (reflected in the published
scientific literature) and the coherence of scientific assessments. Therefore different periods of time may be
necessary for establishing “well established use” of different substances. In any case, however, the period of time
required for establishing a “well established medicinal use” of a constituent of a medicinal product must not be
less than one decade from the first systematic and documented use of that substance as a medicinal product in
the EU.

(b) The documentation submitted by the applicant should cover all aspects of the efficacy assessment and must
include or refer to a review of the relevant literature, taking into account pre- and postmarketing studies and
published scientific literature concerning experience in the form of epidemiological studies and in particular of
comparative epidemiological studies. All documentation, both favourable and unfavourable, should be com-
municated.

(c) Particular attention must be paid to any missing information and justification must be given why demonstration

of efficacy can be supported although some studies are lacking.

(d) The Expert report must explain the relevance of any data submitted which concern a product different from the
product intended for marketing. A judgement must be made whether the product studied can be considered as
similar to the product which will be granted a marketing authorisation in spite of the existing differences.

(e) Post-marketing experience with other products containing the same constituents is of particular importance and

applicants should put a special emphasis on this issue.’