Commission Directive 2000/38/EC of 5 June 2000 amending Chapter Va (Pharmacovigilance) of Council Directive 75/319/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products (Text with EEA relevance)
Date: 2000-06-05
Institutions: European Commission
Subjects: approximation of laws, drug surveillance, pharmaceutical legislation, pharmacology, public health

L 139/28

EN

Official Journal of the European Communities

10.6.2000

COMMISSION DIRECTIVE 2000/38/EC

of 5 June 2000

amending Chapter Va (Pharmacovigilance) of Council Directive 75/319/EEC on the approximation
of provisions laid down by law, regulation or administrative action relating to medicinal products

(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

HAS ADOPTED THIS DIRECTIVE:

Having regard to the Treaty establishing the European
Community,

Having regard to Second Council Directive 75/319/EEC of 20
May 1975 on the approximation of provisions laid down by
law, regulation or administrative action relating to proprietary
medicinal products (1), as
last amended by Directive 93/
39/EEC (2), and in particular Article 29i thereof,

Whereas:

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

In order to ensure the continued safety of medicinal
products in use, it is necessary to ensure that pharmaco-
vigilance systems in the Community are continually
adapted to take account of scientific and technical
progress.

It is necessary to take account of changes arising as a
result of
international harmonisation of definitions,
terminology and technological developments in the field
of pharmacovigilance.

The increasing use of the mutual recognition procedure
established by Directive 75/319/EEC requires
that
current procedures for reporting and dissemination of
suspected adverse drug reactions be amended to ensure
better coordination between Member States.

The increasing use of electronic networks for communi-
cation of information on adverse drug reactions to medi-
cinal products marketed in the Community is intended
to allow competent authorities to share the information
at the same time.

It is necessary to further define terms currently used
within the pharmacovigilance systems.

It is the interst of the Community to ensure that the
centrally authorised
pharmacovigilance
medicinal products and those authorised by other
procedures are consistent.

systems

for

Holders of marketing authorisations should additionally
be proactively responsible for on-going pharmacovigi-
lance of
the medicinal products they place on the
market.

The measures provided for in this Directive are in
conformity with the opinion of the Standing Committee
on Medicinal Products for Human Use,

(1) OJ L 147, 9.6.1975, p. 13.
(2) OJ L 214, 24.8.1993, p. 22.

Article 1

Chapter Va (Pharmacovigilance) of Directive 75/319/EEC is
hereby amended as follows:

1. In Article 29a, the third paragraph is hereby replaced by the

following text:

‘This system shall also take into account any available infor-
mation on misuse and abuse of medicinal products which
may have an impact on the evaluation of their benefits and
risks.’

2. Article 29b is hereby replaced by the following text:

‘Article 29b

For the purpose of this Directive, the following definitions
shall apply:

(a) adverse reaction means a response to a medicinal product
which is noxious and unintended and which occurs at
doses normally used in man for the prophylaxis, diag-
nosis or therapy of disease or for the restoration, correc-
tion or modification of physiological function;

(b) serious adverse action means an adverse action which
results in death,
is life-threatening, requires inpatient
hospitalisation or prolongation of existing hospitalisa-
tion, results in persistent or significant disability or inca-
pacity, or is a congential anomaly/birth defect;

(c) unexpected adverse reaction means an adverse reaction, the
nature, severity or outcome of which is not consistent
with the summary of product characteristics;

(d) periodic safety update reports means the periodical reports
containing the records referred to in Article 29d;

(e) post-authorisation safety study means a pharmacoepide-
miological study or a clinical trial carried out in accord-
ance with the terms of the marketing authorisation,
conducted with the aim of identifying or quantifying a
safety hazard relating to an authorised medicinal
product;

(f) abuse of medicinal products means persistent or spor-
adic,
intentional excessive use of medicinal products
which is accompanied by harmful physical or psycho-
logical effects.

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EN

Official Journal of the European Communities

L 139/29

the definitions and principles
For the interpretation of
outlined in this chapter, the marketing authorisation holder
and the competent authorities shall refer to the guidance
referred to in Article 29g.’

3. Article 29c is hereby amended as follows:

(a) in the first paragraph the words ‘person responsible for
placing the medicinal product on the market’ are
changed to ‘marketing authorisation holder’;

(b) in point (a) of the second paragraph the words ‘at a
single’ are changed to ‘in order to be accessible at least
at one’;

(c) in point (b) of the second paragraph the words ‘relevant
national or Community guidance’ are changed to
‘guidance referred to in Article 29g’;

(d) to the second paragraph the following point

(d)

is

added:

‘d) the provision to the competent authorities, of any
other information relevant to the evaluation of the
benefits and risks afforded by a medicinal product,
including appropriate information on post-author-
isation safety studies.’

4. Article 29d is hereby replaced by the following text:

‘Article 29d

1.
The marketing authorisation holder shall be required
to maintain detailed records of all suspected adverse reac-
tions occurring either in the Community or in a third
country.

The marketing authorisation holder shall be required
2.
to record and to report all suspected serious adverse reac-
tions which are brought to his attention by a health care
professional immediately to the competent authority of the
Member State in whose territory the incident occurred, and
in no case later than 15 calendar days following the receipt
of the information.

3.
The marketing authorisation holder shall be required
to record and report all other suspected serious adverse
reactions which meet the reporting criteria in accordance
with the guidance referred to in Article 29g of which he can
reasonably be expected to have knowledge immediately to
the competent authority of the Member State in whose
territory the incident occurred, and in no case later than 15
calendar days following the receipt of the information.

4.
The marketing authorisation holder shall ensure that
all suspected serious unexpected adverse reactions occurring
to his
in the territory of a third country and brought
attention by a health care professional are reported imme-
diately in accordance with the guidance referred to in
Article 29g, so that they are available to the Agency and to
the competent authorities of the Member States where the
medicinal product is authorised, and in no case later than
15 calendar days following the receipt of the information.

5.
In the case of medicinal products which have been
considered within the scope of Directive 87/22/EEC, or
which have benefited from the procedures of mutual recog-

nition foreseen in Articles 7 and 7a of Directive 65/65/EEC,
Article 9(4) of this Directive, and medicinal products for
which there has been a referral to the procedures foreseen
by Articles 13 and 14 of this Directive, the marketing
authorisation holder
shall additionally ensure that all
reactions occurring in the
suspected serious
Community are reported in the format and at intervals to be
agreed with the reference Member State, or a competent
authority acting as the reference Member State, in such a
way so as to be accessible to the reference Member State.

adverse

6.
Unless other requirements have been laid down as a
condition of the granting of authorisation, or subsequently
as indicated in the guidance referred to in Article 29g,
records of all adverse reactions shall be submitted to the
competent authorities in the form of a periodic safety
update report, either immediately upon request or periodi-
cally as follows: six monthly for the first two years after
authorisation, annually for the subsequent two years, and at
the time of the first renewal. Thereafter the periodic safety
update reports shall be submitted at five-yearly intervals
together with the application for renewal of the author-
isation. The periodic safety update reports shall include a
scientific evaluation of the benefit and risks afforded by the
medicinal products.

7.
Following the granting of a marketing authorisation,
the marketing authorisation holder may request the amend-
ment of the periods referred to in this article according to
the procedure laid down by Commission Regulation (EC)
No 541/95 (*).

(*) OJ L 55, 11.3.1995, p. 7.’

5. In Article 29e,

‘medical
practitioners’ are changed to ‘doctors and other health
care professionals’:

second paragraph,

the words

6. Article 29f is hereby replaced by the following text:

‘Article 29f

The Agency,

in collaboration with the Member
1.
States and the Commission shall set up a data-processing
network to facilitate the exchange of pharmacovigilance
information regarding medicinal products marketed in the
Community intended to allow all competent authorities
to share the information at the same time.

2. Making use of
the network foreseen in the first
paragraph, Member States shall ensure that reports of
suspected serious adverse reactions that have taken place
on their territory are immediately made available to the
Agency and the other Member States, and in any case
within 15 calendar days of their notification, at the latest.

shall ensure that

The Member States

3.
reports of
suspected serious adverse reactions that have taken place
on their territory are immediately made available to the
marketing authorisation holder, and in any case within
15 calendar day of their notification, at the latest.’

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Official Journal of the European Communities

10.6.2000

7. Article 29g is hereby replaced by the following text:

Article 2

‘Article 29g

(a) In order

in

consultation with

to facilitate the exchange of

information
about pharmacovigilance within the Community, the
the Agency,
Commission,
Member States and interested parties, shall draw up
guidance on the collection, verification and presenta-
tion of adverse reaction reports,
including technical
requirements for electronic exchange of pharmacovigi-
lance information in accordance with internationally
agreed formats and shall publish a reference to an
internationally agreed medical terminology.

(b) This guidance shall be published in Volume 9 of the
Rules governing medicinal products in the European
Union and shall take account of international harmo-
nisation work carried out in the field of pharmacovi-
gilance.’

8. Article 29h is hereby replaced by the following text:

‘Article 29h

Where, as a result of the evaluation of pharmacovigilance
data, a Member State considers that a marketing author-
isation shold be suspended, withdrawn or varied in
accordance with the guidance referred to in Article 29g,
it shall forthwith inform the Agency, the other Member
States and the marketing authorisation holder.

In case of urgency,
the Member State concerned may
a medicinal
suspend the marketing authorisation of
product, provided the Agency, the Commission and the
other Member States are informed at
the latest on the
following working day.’

Member States shall bring into force the laws, regulations
and administrative provisions necessary to comply with this
Directive no later than 5 December 2001.

the provisions set out

When the Member States adopt
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 references
shall be adopted by the Member States. The Member States
shall communicate to the Commission the provisions of
national
law which they adopt in the field covered by this
Directive.

Article 3

This Directive shall enter
into force on the 20th day
following its publication in the Official Journal of the European
Communities.

Article 4

This Directive is adressed to the Member States.

Done at Brussels, 5 June 2000.

For the Commission

Erkki LIIKANEN

Member of the Commission