Proposal for a Directive of the European Parliament and of the Council amending Directive 2001/83/EC on the Community code relating to medicinal products for human use
Date: 2001-11-26
Institutions: European Commission
Subjects: drug surveillance, market approval, medicinal product, pharmaceutical legislation

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Proposal for a Directive of the European Parliament and of the Council amending Directive
2001/83/EC on the Community code relating to medicinal products for human use

(2002/C 75 E/13)

COM(2001) 404 final (cid:151) 2001/0253(COD)

(Submitted by the Commission on 26 November 2001)

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE
EUROPEAN UNION,

Having regard to the Treaty establishing the European
Community, and in particular Article 95 thereof,

Having regard to the proposal by the Commission,

the authorisation and supervision of medicinal products
for human and veterinary use and establishing a European
the Evaluation of Medicinal Products (1)
Agency for
provides that, within six years of
its entry into force,
the Commission is required to publish a general report
on the experience acquired as a result of the operation of
the marketing authorisation procedures laid down in that
Regulation and in other Community legal provisions.

Having regard to the opinion of
Committee,

the Economic and Social

Having regard to the opinion of the Committee of the Regions,

(6) In the light of the Commission’s report on the experience
acquired,
the
operation of the marketing authorisation procedures for
medicinal products in the Community.

it has proved necessary to improve

Acting in accordance with the procedure laid down in Article
251 of the Treaty,

Whereas:

(1) Directive 2001/83/EC of the European Parliament and of
the Council of 23 October 2001 on the Community code
in the
relating to medicinal products for human use,
and
clarity and rationalisation,
interests of
combines in a single text the texts of Community legis-
lation on medicinal products for human use.

codifies

(2) Community legislation is a major milestone in the
achievement of the objective of the free movement of
medicinal products for human use and the elimination
of obstacles to trade in such products. However, in the
light of
the experience acquired, new measures have
proved necessary to eliminate the remaining obstacles to
free movement.

(3) It is therefore necessary to align the national laws, regu-
and administrative provisions which contain
lations
differences with regard to the basic principles in order
to promote the operation of the internal market.

(4) The main purpose of any regulation on the production
and distribution of medicinal products for human use
should be to safeguard public health. However,
this
objective should be achieved by means which do not
industry
hinder the development of the pharmaceutical
or trade in medicinal products in the Community.

In order

sector and other

to take account, both of

(7) Particularly as a result of scientific and technical progress,
the definitions and scope of Directive 2001/83/EC should
be clarified in order to achieve high standards for the
quality, safety and efficacy of medicinal products for
the
human use.
emergence of new therapies and of the growing number
of so-called (cid:145)borderline(cid:146) products between the medicinal
product
the definition of
(cid:145)medicinal product(cid:146) should be modified so as to avoid
to the applicable legislation, when a
any doubt as
product, whilst
fully falling within the definition of a
medicinal product, may also fall within the definition of
other regulated products. Also, taking into account the
legislation, provision
characteristics of pharmaceutical
should be made that such legislation is to apply.
It is
this opportunity to
also worth taking advantage of
improve the consistency of
the terminology of phar-
maceutical legislation.

sectors,

(8) Wherever it

is proposed to change the scope of

the
centralised procedure, it should no longer be possible to
opt for the mutual-recognition or decentralised procedure
in respect of new active substances. On the other hand,
with regard to generic medicinal products of which the
reference medicinal product has obtained a marketing
authorisation under the centralised procedure, applicants
seeking marketing authorisation should be able to choose
the two procedures, on certain conditions.
either of
the mutual-recognition
Similarly,
decentralised
procedure
an option for
should be
medicinal products which represent a therapeutic inno-
vation or which are of benefit to Society or to patients.

available

or

as

(5) Article 71 of Council Regulation (EEC) No 2309/93 of
22 July 1993 laying down Community procedures for

(1) OJ L 214, 21.8.1993, p. 1; Regulation as amended by Commission

Regulation (EC) No 649/98 (OJ L 88, 24.3.1998, p. 7).

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the operation of marketing author-
(9) The evaluation of
isation procedures
the need to revise most
reveals
particularly the mutual recognition procedure in order
to improve the opportunities for cooperation between
should be
Member States. This cooperation process
formalised by setting up a coordination group for this
procedure and by defining its operation so as to settle
disagreements within the framework of a revised decen-
tralised procedure.

(10) With regard to referrals, the experience acquired reveals
the need for an appropriate procedure, particularly in the
case of referrals relating to an entire therapeutic class or
to all medicinal products containing the same active
substance.

(11) Since generic medicines account for a major part of the
market
to the
Community market should be facilitated in the light of
the experience acquired.

in medicinal products,

access

their

(12) The criteria of quality, safety and efficacy should enable
the risk/benefit balance of all medicinal products to be
assessed both when they are placed on the market and
for
In this
subsequent monitoring.
it is necessary to harmonise and adapt the
connection,
criteria
suspension and withdrawal of
for
marketing authorisations.

the purposes of

refusal,

(13) The validity of marketing authorisations should no longer
be limited to five years. On the other hand, market
surveillance should be stepped up. In addition, any auth-
orisation which does not lead to the actual placing on the
market of a medicinal product should cease to be valid.

(14) The quality of medicinal products

for human use
produced or available in the Community should be
guaranteed by requiring that the active substances used
in their composition comply with the principles of good
manufacturing practice in relation to those medicinal
products.
the
Community provisions on inspections and to compile a
Community register of the results of those inspections.

It has proved necessary to reinforce

(15) Pharmacovigilance

and, more

generally, market
failure to
surveillance and sanctions in the event of
comply with the provisions should be stepped up.
In
the field of pharmacovigilance, account should be taken
of the facilities offered by new information technologies
to improve exchanges between Member States.

information
experience acquired. On the other hand,
relating to certain medicinal products
is authorised
under strict conditions in the interests of patients and in
order to meet their legitimate needs and expectations.
Such information should not be equated with direct
advertising or marketing of prescription medicines.

(17) Since most of the measures necessary for the implemen-
tation of this Directive are measures of individual scope,
use should be made of
the advisory procedure under
Article 3 of Council Decision 1999/468/EC of 28 June
1999 laying down the procedures for the exercise of
implementing powers conferred on the Commission (1),
the management procedure under Article 4
or of
thereof. As regards measures of general scope within the
meaning of Article 2 of the Decision, those measures
should be adopted by use of the regulatory procedure
provided for in Article 5 thereof.

(18) Directive 2001/83/EC should be amended accordingly,

HAVE ADOPTED THIS DIRECTIVE:

Article 1

Directive 2001/83/EC is amended as follows:

1. Article 1 is amended as follows:

(a) Point 1 is deleted.

(b) Point 2 is replaced by the following:

(cid:145)2. Medicinal product:

(a) Any substance or combination of substances
presented as having properties for treating or
preventing disease in human beings.

(b) Any substance or combination of substances
which may be used in human beings with a
view to making a medical diagnosis or
to
restoring, correcting or modifying physiological
functions.(cid:146)

(c) Point 20 is replaced by the following:

(cid:145)20. Name of the medicinal product:

The name, which may be either an invented name
not liable to confusion with the common name,
or a common or scientific name accompanied by
a trade mark or the name of the marketing auth-
orisation holder.(cid:146)

(16) As part of the proper use of medicinal products, the rules
on packaging should be adapted to take account of the

(1) OJ L 184, 17.7.1999, p. 23.

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2. Article 2 is replaced by the following:

(b) The following paragraph 1(a) is inserted:

(cid:145)Article 2

The marketing authorisation holder shall be

(cid:145)1a.
responsible for marketing the medicinal product.(cid:146)

The provisions of

1.
this Directive shall apply to
medicinal products for human use intended to be placed
on the market
in Member States and either prepared
industrially or manufactured by a method involving an
industrial process.

2. Whenever a substance or combination of substances
falls within the definition of
the
this Directive shall apply, even in cases
provisions of
where the substance or combination of substances falls
also within the scope of other Community legislation.(cid:146)

(cid:147)medicinal product(cid:148),

3. Article 3 is amended as follows:

(a) Point 3 is replaced by the following:

(cid:145)3. Medicinal products

intended for

research and
development trials, but without prejudice to the
provisions
the
of Directive 2001/20/EC of
European Parliament and of the Council (*);

___________
(*) OJ L 121, 1.5.2001, p. 34.(cid:146)

6. Article 8(3) is amended as follows:

(a) Points (b) and (c) are replaced by the following:

(cid:145)(b) Name of the medicinal product.

(c) Qualitative and quantitative particulars of all the

constituents of the medicinal product.(cid:146)

(b) Points (h), (i) and (j) are replaced by the following:

(cid:145)(h) Description of the control methods employed by

the manufacturer.

(i) Results of:

(cid:151) pharmaceutical (physico-chemical, biological or

microbiological) tests,

(cid:151) pre-clinical (toxicological and pharmacological)

tests,

(b) Point 6 is replaced by the following:

(cid:151) clinical trials.

(cid:145)6. Whole blood, plasma or blood cells of human
origin, except for plasma which is prepared by a
method involving an industrial process.(cid:146)

4. Article 5 is replaced by the following:

(cid:145)Article 5

Without prejudice to Regulation [(EEC) No 2309/93], a
in accordance with legislation in
Member State may,
force and to fulfil
special needs, exclude from the
provisions of this Directive medicinal products supplied
in response to a bona fide unsolicited order, formulated
in accordance with the specifications of an authorised
health care professional and for use by his individual
patients under his direct personal responsibility.(cid:146)

(j) A summary, in accordance with Article 11, of the
the outer
product characteristics, a mock-up of
packaging,
foreseen in
containing the details
Article 54 and of the immediate packaging of the
medicinal product, containing the details foreseen
in Article 55 together with a package leaflet in
accordance with Article 59.(cid:146)

(c) The following point (m) is added:

(cid:145)(m) A copy of any designation of

the medicinal
product as an orphan medicinal product under
Regulation (EC) No 141/2000 of the European
Parliament and of the Council (*), accompanied
by a copy of the relevant Agency opinion.

5. Article 6 is amended as follows:

___________
(*) OJ L 18, 22.1.2000, p. 1.(cid:146)

(a)

In paragraph 1, the following second subparagraph is
added:

(d) The following third subparagraph is added:

(cid:145)The various strengths, pharmaceutical forms, adminis-
tration routes, presentations and any variation under
Article 35 shall be
first
subparagraph and shall be considered as part of the
same authorisation.(cid:146)

authorised under

the

(cid:145)The documents and information concerning the results
of the pharmaceutical and pre-clinical tests and the
the first
clinical
subparagraph shall be
detailed
accompanied
summaries
in accordance with the provisions of
Article 12.(cid:146)

referred to in point

(i) of
by

trials

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7. Article 10 is replaced by the following:

(cid:145)Article 10

1.
By way of derogation from point (i) of Article 8(3),
and without prejudice to the law relating to the protection
of industrial and commercial property, the applicant shall
not be required to provide the results of pre-clinical tests
the
or of clinical
medicinal product has been a generic of a reference
medicinal product authorised under Article 6 for not less
than ten years in a Member State or in the Community.

trials if he/she can demonstrate that

those ten years,

The ten-year period referred to in the first subparagraph
shall be extended to 11 years if, during the first eight years
of
the marketing authorisation holder
obtains an authorisation for one or more new therapeutic
indications which, during the scientific evaluation prior to
their authorisation, are held to bring a significant clinical
benefit in comparison with existing therapies.

2.

For the purposes of this Article:

(a) reference medicinal product shall mean a medicinal
in accordance

product authorised under Article 6,
with the provisions of Article 8;

(b) generic medicinal product

shall mean a medicinal
product which has the same qualitative and quanti-
tative composition in active principles and the same
pharmaceutical form, and whose bioequivalence with
the reference medicinal product has been demonstrated
various
by
are
immediate-release
deemed to be one and the same pharmaceutical
form. Bioavailability studies may not be required of
the applicant
the
product meets the criteria of Annex I.

if he/she can demonstrate that

appropriate bioavailability

oral pharmaceutical

tests. The

forms

The first subparagraph of paragraph 1 shall not apply
3.
to changes in the active substance(s),
therapeutic indi-
cations, strength, pharmaceutical form or route of adminis-
tration vis-(cid:224)-vis the reference medicinal product, and the
results of appropriate pre-clinical
trials
shall be provided.

tests or clinical

Conducting the necessary tests and trials with a view
4.
to application of paragraphs 1, 2 and 3 to a generic
medicinal product shall not be regarded as contrary to
patent rights or to complementary protection certificates
for those medicinal products.(cid:146)

8. The following Articles 10a to 10c are inserted:

(cid:145)Article 10a

trials

if he/she

can demonstrate

be required to provide the results of pre-clinical tests and
clinical
the
component(s) of the medicinal product have been of well
established medicinal use within the Community for at
least the last ten years, with recognised efficacy and an
acceptable level of safety in terms of the conditions set
out in Annex I. In that event, the test and trial results
shall be replaced by appropriate scientific literature.

that

Article 10b

in the

composition of

In the case of new medicinal products containing active
substances used
authorised
medicinal products but not hitherto used in combination
for therapeutic purposes, the results of pre-clinical tests
and clinical trials relating to that combination shall be
provided, but it shall not be necessary to provide scientific
references relating to each individual active substance.

Article 10c

pre-clinical

Following issuance of a marketing authorisation, the auth-
orisation holder may allow use to be made of the phar-
maceutical,
documentation
and
contained in the file on the medicinal product, with a
view to examining subsequent applications relating to
other medicinal products possessing the same qualitative
and quantitative composition in terms of active substances
and the same pharmaceutical form.(cid:146)

clinical

9. Article 11 is amended as follows:

(a) Point 1 is replaced by the following:

(cid:145)1. Name of the medicinal product, followed by the

strength and the pharmaceutical form;(cid:146)

(b) Point 6 is replaced by the following:

(cid:145)6. Pharmaceutical particulars:

6.1. excipients,

6.2. shelf life, when necessary after reconstitution
of
the medicinal product or when the
immediate packaging is opened for the first
time,

6.3. special precautions for storage,

6.4. nature and contents of immediate packaging,

6.5. special precautions

for disposal of unused
medicinal products or waste materials derived
from such medicinal products, if appropriate.(cid:146)

By way of derogation from point (i) of Article 8(3), and
without prejudice to the law relating to the protection of
industrial and commercial property, the applicant shall not

(c) The following paragraph 10 is added:

(cid:145)10. Classification in accordance with Article 70.(cid:146)

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10. Article 12 is replaced by the following:

14. Article 16 is amended as follows:

(cid:145)Article 12

The applicant shall ensure that, before the detailed
1.
summaries referred to in point
(j) of Article 8(3) are
submitted to the competent authorities, they have been
drawn up and signed by experts with the necessary
technical or professional qualifications, which should be
set out in a brief curriculum vitae.

Persons having the technical and professional qualifi-
justify any use
in

2.
cations referred to in paragraph 1 shall
made of
accordance with the conditions set out in Annex I.

scientific literature under Article 10a(1)

3.
The detailed summaries shall form part of the file
which the applicant submits to the competent authorities.(cid:146)

11. Article 13 is replaced by the following:

(cid:145)Article 13

shall

States

ensure

1. Member
that homeopathic
medicinal products manufactured and placed on the
market within the Community are registered or authorised
in accordance with Articles 14, 15 and 16, except where
such medicinal products are covered by a registration or
authorisation issued in accordance with national legislation
up to 31 December 1993.

2. Member States shall establish a special simplified
registration procedure for
the homeopathic medicinal
products referred to in Article 14.(cid:146)

12. Article 14 is amended as follows:

(a)

In paragraph 1,
(cid:145)Article 8 and Articles 10 to 11(cid:146).

(cid:145)Articles 8, 10 and 11(cid:146) is replaced by

(b) In paragraph 2,

(cid:145)toxicological and pharmacological(cid:146) is

replaced by (cid:145)pre-clinical(cid:146).

15. Articles 17 and 18 are replaced by the following:

(cid:145)Article 17

1. Member States shall take all appropriate measures to
ensure that the procedure for granting an authorisation to
place a medicinal product on the market is completed
within 150 days of the submission of a valid application,
including 120 days for drawing up the assessment report
and the summary of the product characteristics.

With a view to granting a marketing authorisation in two
or more Member States in respect of the same medicinal
product, applications shall be submitted in accordance
with Articles 27 to 39.

2. Where a Member State notes that another marketing
authorisation application for the same medicinal product is
the Member
being examined in another Member State,
State concerned shall decline to assess the application
and shall advise the applicant that the procedure set out
in Articles 27 to 39 is applicable.

Article 18

Where a Member State is informed in accordance with
point (m) of Article 8(3) that another Member State has
authorised a medicinal product which is the subject of a
marketing authorisation application in the Member State
concerned, it shall reject the application unless it has been
submitted in compliance with Articles 27 to 39.(cid:146)

(a)

In paragraph 1, the following second subparagraph is
inserted:

16. Article 19 is amended as follows:

(cid:145)If new scientific evidence so warrants, the Commission
may amend the third indent of the first subparagraph
by the procedure referred to in Article 121(2).(cid:146)

(a)

In the introductory sentence,
replaced by (cid:145)Article 8 and Articles 10 to 10(c)(cid:146).

(cid:145)Articles 8 and 10(1)(cid:146) is

(b) Paragraph 3 is deleted.

(b) In point 1, (cid:145)Articles 8 and 10(1)(cid:146) is replaced by (cid:145)Article

8 and Articles 10 to 10c(cid:146).

13. In Article 15, the sixth indent is replaced by the following:

(c)

In point 3,
(cid:145)Article 8(3) and Articles 10 to 10c(cid:146).

(cid:145)Articles 8(3) and 10(1)(cid:146)

is replaced by

(cid:145)(cid:151) one or more mock-ups of the outer packaging and
the immediate packaging of the medicinal products to
be registered,(cid:146)

17.

In point (b) of Article 20,
cases(cid:146) is replaced by (cid:145)in justifiable cases(cid:146).

(cid:145)in exceptional and justifiable

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18. In Article 21, paragraphs 3 and 4 are replaced by the

22. Article 26 is replaced by the following:

following:

(cid:145)3.
The competent authorities shall make available to
any interested party a copy of the authorisation together
with the summary of the product characteristics.

The

competent

the pharmaceutical and pre-clinical

4.
shall draw up an
authorities
assessment report and comments on the file as regards
the results of
tests
and the clinical trials of the medicinal product concerned.
The assessment report shall be updated whenever new
information becomes available which is of
importance
for the evaluation of the quality, safety or efficacy of the
medicinal product concerned.

At the request of any interested party, the competent auth-
orities shall make available the assessment report, together
with the reasons
their opinion, after deletion of
information of a commercially confidential nature.(cid:146)

for

19. Article 22 is replaced by the following:

(cid:145)Article 22

In exceptional circumstances, and following consultation
with the applicant, an authorisation may be granted
subject to certain specific obligations to carry out further
studies following the granting of authorisation.

(cid:145)Article 26

The marketing authorisation shall be refused if, after verifi-
cation of the particulars and documents listed in Article 8
and Articles 10 to 10c, it is clear that:

(a) the risk/benefit balance is not considered to be

favourable; or

(b) its therapeutic efficacy is insufficiently substantiated by

the applicant; or

(c)

its qualitative and quantitative composition is not as
declared.

Authorisation shall
likewise be refused if the particulars
and documents submitted in support of the application
do not comply with Article 8 and Articles 10 to 10c.(cid:146)

23. The heading of Chapter 4 of Title III is replaced by the

following:

(cid:145)CHAPTER 4

Mutual
procedure(cid:146).

recognition procedure

and decentralised

24. Articles 27 to 32 are replaced by the following:

Such authorisations may be granted only for objective and
verifiable reasons and shall be based on one of the causes
referred to in Part 4 G of Annex I.(cid:146)

(cid:145)Article 27

20. In Article 23, the following third paragraph is added:

(cid:145)In order that the risk-benefit balance may be continuously
assessed after the issue of a marketing authorisation, any
information modifying the content of the file and any new
information not appearing in the original
file shall be
forwarded to the competent authorities.(cid:146)

21. Article 24 is replaced by the following:

(cid:145)Article 24

A coordination group is hereby set up for the exam-
1.
ination of any question relating to marketing authorisation
of a medicinal product in two or more Member States in
accordance with the procedures laid down in this Chapter.
this coor-
The Agency shall provide the secretariat of
dination group.

2.
The coordination group shall be composed of one
representative per Member State appointed for a term of
three years, which shall be renewable. Members of the
coordination group may arrange to be accompanied by
experts.

1. Without prejudice
marketing authorisation shall be valid indefinitely.

to paragraphs 2 and 3,

a

The coordination group shall draw up its own Rules
3.
of Procedure, which shall enter into force after a favourable
opinion of the Commission.

Any authorisation which is not followed within two
2.
years of its issue by the actual placing on the market of the
authorised product in the authorising Member State shall
cease to be valid.

3. When an authorised product previously placed on
the market in the authorising Member State is no longer
actually present on the market
two
consecutive years, the authorisation for that product shall
cease to be valid.(cid:146)

for a period of

Article 28

1. With a view towards the grant of a marketing auth-
orisation for a medicinal product
in more than one
Member State, an applicant shall submit an application
based on an identical dossier in these Member States.
The dossier shall contain the information and documents
referred to in Article 8 and Articles 10 to 11. The
documents
include a list of Member
States concerned by the application.

submitted shall

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The applicant shall request one Member State to act as
(cid:147)reference Member State(cid:148) and to prepare an assessment
report on the medicinal product according to paragraphs
2 or 3.

Where appropriate, the assessment report shall contain an
analysis for the purposes of the second subparagraph of
Article 10(1).

the time of application,

2. Where the medicinal product has already received a
marketing authorisation at
the
Member States concerned shall recognise the marketing
authorisation granted by the reference Member State. To
this end, the marketing authorisation holder shall request
the reference Member State either to prepare an assessment
report on the medicinal product or, if necessary, to update
any existing assessment report. The reference Member
State shall prepare or update the assessment
report
within 60 days of
the application. The
receipt of
assessment report together with the summary of product
characteristics
to the Member States
sent
concerned and to the applicant.

shall be

The points of disagreement shall be forthwith referred to
the coordination group.

2. Within the coordination group, all Member States
referred to in paragraph 1 shall use their best endeavours
to reach agreement on the action to be taken. They shall
allow the applicant the opportunity to make his/her point
of view known orally or in writing. If, within 60 days of
the communication of the elements of disagreement, the
Member States reach an agreement, the reference Member
State shall record the broad agreement, close the procedure
and inform the applicant accordingly. Article 28(5) shall
apply.

If

the Member States fail

3.
to reach an agreement
within the 60-day period laid down in paragraph 2, the
Agency shall be immediately informed, with a view to the
application of the procedure under Article 32. The Agency
shall be provided with a detailed statement of the matters
on which the Member States have been unable to reach
agreement and the reasons for their disagreement. A copy
shall be forwarded to the applicant.

shall

In cases where the medicinal product has not
3.
time of
the
received a marketing authorisation at
application,
the reference
request
the applicant
Member State to prepare a draft assessment report, a
draft summary of product characteristics, and a draft of
the labelling and package leaflet. The reference Member
State shall prepare these draft documents within 120
days of receipt of a valid application and shall send them
to the concerned Member States and to the applicant.

4. Within 90 days of receipt of the documents referred
to in paragraphs 2 and 3, the Member States concerned
shall approve the assessment
the summary of
product characteristics, and the labelling and package
inform the reference Member State to
leaflet and shall
this effect. The reference Member State shall record the
agreement of all parties, close the procedure and inform
the applicant accordingly.

report,

5.
Each Member State where an application has been
submitted in accordance with paragraph 1 shall adopt a
decision in conformity with the approved assessment
report, the summary of product characteristics and the
labelling and package leaflet as approved, within 30 days
of acknowledgement of the agreement.

Article 29

1.
If, within the period laid down in Article 28(4), a
Member State cannot approve the assessment report, the
summary of product characteristics, the labelling and the
package leaflet on the grounds of serious potential risk to
public health,
it shall give a detailed exposition of the
reasons for its position to the reference Member State, to
the other Member States concerned and to the applicant.

4.
As soon as the applicant is informed that the matter
has been referred to the Agency, he/she shall forthwith
forward to the Agency a copy of the information and
particulars referred to in the first subparagraph of Article
28(1).

5.
In the circumstances referred to in paragraph 3,
Member States that have approved the assessment report,
the draft summary of product characteristics and the
labelling and package leaflet of
the reference Member
State may, at the request of the applicant, authorise the
medicinal product without waiting for the outcome of the
procedure laid down in Article 32. In that event, the auth-
orisation granted shall be without prejudice
to the
outcome of that procedure.

Article 30

1.
If two or more applications submitted in accordance
with Article 8 and Articles 10 to 11 have been made for
marketing authorisation for a particular medicinal product,
and if Member States have adopted divergent decisions
concerning the authorisation of the medicinal product or
its
the
suspension or withdrawal, a Member State,
Commission or the applicant or the marketing author-
isation holder may refer the matter to the Committee on
Human Medicinal Products, hereinafter referred to as (cid:147)the
Committee(cid:148), for application of the procedure laid down in
Article 32.

In order to promote harmonisation of authorisations
2.
for medicinal products authorised for not less than ten
years in the Community, Member States may, each year,
forward to the coordination group a list of medicinal
products for which a harmonised summary of product
characteristics should be drawn up.

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The coordination group shall lay down a list taking into
account the proposals from all Member States and shall
forward this list to the Commission.

The Commission or a Member State, in agreement with the
Agency and taking into account the views of interested
parties, may refer
in accordance with
these products
paragraph 1.

Article 31

the Commission or

The Member States or

the
1.
applicant or the marketing authorisation holder may,
in
specific cases where the interests of the Community are
involved, refer the matter to the Committee for application
of
the procedure laid down in Article 32 before any
decision is reached on a request for a marketing author-
isation or on the suspension or withdrawal of an author-
isation, or on any other variation to the terms of a
marketing authorisation which appears necessary,
in
particular to take account of the information collected in
accordance with Title IX.

The Member State concerned or the Commission shall
clearly identify the question which is referred to the
Committee
inform the
applicant or the marketing authorisation holder.

consideration and shall

for

The Member States and the applicant or the marketing
authorisation holder shall supply the Committee with all
available information relating to the matter in question.

to the Committee concerns a
2. Where the referral
range of medicinal products or a therapeutic class, the
Agency may limit the procedure to certain specific parts
of the authorisation.

In that event, Article 35 shall apply to those medicinal
products only if they were covered by the authorisation
procedures referred to in this Chapter.

Article 32

1. When reference is made to the procedure laid down
in this Article, the Committee shall consider the matter
concerned and shall issue a reasoned opinion within 60
days of the date on which the matter was referred to it.

in cases

submitted to the Committee

However,
in
accordance with Articles 30 and 31, this period may be
extended by the Committee for a further period of up to
90 days, taking into account the views of the applicants or
the marketing authorisation holders concerned.

In an emergency, and on a proposal from its Chairman,
the Committee may agree to a shorter deadline.

In order to consider the matter, the Committee may
2.
appoint one of
its members to act as rapporteur. The
Committee may also appoint individual experts to advise
it on specific questions. When appointing experts,
the
and specify the
Committee
time-limit for the completion of these tasks.

shall define

tasks

their

Before issuing its opinion,

3.
the Committee shall
the marketing authorisation
provide the applicant or
holder with an opportunity to present written or oral
explanations.

The opinion of the Committee shall be accompanied by a
draft summary of product characteristics for the product
and a draft text of the labelling and package leaflet.

If necessary,
the Committee may call upon any other
person to provide information relating to the matter
before it.

The Committee may suspend the time-limits referred to in
paragraph 1 in order
the
marketing authorisation holder to prepare explanations.

to allow the applicant or

4.
The Agency shall forthwith inform the applicant or
the marketing authorisation holder where the opinion of
the Committee is that:

(a) the application does not satisfy the criteria for author-

isation; or

(b) the summary of the product characteristics proposed
by the applicant or the marketing authorisation holder
in accordance with Article 11 should be amended; or

(c)

the authorisation should be granted subject to certain
conditions, in view of conditions considered essential
for the safe and effective use of the medicinal product
including pharmacovigilance; or

(d) a marketing authorisation should be suspended, varied

or withdrawn.

Within 15 days of receipt of the opinion, the applicant or
the marketing authorisation holder may notify the Agency
in writing of his intention to appeal. In that case, he/she
shall
to the
forward the detailed grounds for appeal
Agency within 60 days of receipt of the opinion. Within
the
60 days of
Committee shall
its opinion according to
Article 53(1) of Regulation (EEC) No 2309/93. The
conclusions reached on the appeal shall be annexed to
the assessment report referred to in paragraph 5 of this
Article.

the grounds

for appeal,

receipt of

reconsider

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its adoption, the Agency shall
5. Within 30 days of
forward the final opinion of
the Committee to the
Member States, to the Commission and to the applicant
together with a
or the marketing authorisation holder,
the medicinal
assessment of
report describing
product and stating the reasons for its conclusions.

the

In the event of an opinion in favour of granting or main-
taining an authorisation to place the medicinal product
concerned on the market, the following documents shall
be annexed to the opinion:

(a) a draft summary of

the product characteristics, as

referred to in Article 11;

(b) any conditions affecting the authorisation within the

meaning of point (c) of paragraph 4;

(c)

the proposed text of the labelling and leaflet.(cid:146)

25. Article 33 is amended as follows:

(a)

In the second paragraph,
replaced by (cid:145)Article 32(5) second indent(cid:146).

(cid:145)Article 32(5)(a) and (b)(cid:146)

is

(b) In the fourth paragraph, the words (cid:145)or the marketing
the word
are

added after

authorisation holder(cid:146)
(cid:145)applicant(cid:146).

deadline taking into account
involved;

the degree of urgency

(c) Member States shall have the option of submitting a
written request that the draft Decision be discussed in
a plenary meeting of the Standing Committee.

Where,
in the opinion of the Commission, the written
observations of a Member State raise important new
questions of a scientific or technical nature which have
not been addressed in the opinion delivered by the
Agency, the Chairman shall suspend the procedure and
further
the application back to the Agency for
refer
consideration.

The provisions necessary for the implementation of this
paragraph shall be adopted by the Commission in
accordance with the procedure referred to in Article
121(2).

States

The decision as referred to in paragraph 1 shall be
3.
addressed to all Member
and reported for
information to the marketing authorisation holder or
applicant. The Member
the
reference Member State shall either grant or withdraw
marketing authorisation, or vary its terms as necessary
to comply with the decision within 30 days following its
notification, and they shall refer to it. They shall inform
the Commission and the Agency accordingly.(cid:146)

concerned

States

and

26. Article 34 is replaced by the following:

27. The third subparagraph of Article 35(1) is deleted.

(cid:145)Article 34

28. In Article 38, paragraph 2 is replaced by the following:

1.
The Commission shall make a final decision in
accordance with the procedure referred to in Article
121(3), where the draft decision is in conformity with
the Agency’s opinion.

The Commission shall make a final decision in accordance
with the procedure referred to in Article 121(4), where the
in conformity with the Agency’s
draft decision is not
opinion.

2.
The rules of procedure of the Standing Committee
established by Article 121(1) shall be adjusted to take
the tasks incumbent upon it in accordance
account of
with this Chapter.

Those adjustments shall entail the following provisions:

(a) except in cases referred to in the third paragraph of
the Standing Committee

Article 33, the opinion of
shall be given in writing;

(b) Member States shall be allowed 15 days to forward
written observations on the draft decision to the
Commission. However, in cases where the decision is
of an urgent nature, the Chairman may set a shorter

No later than [date], the Commission shall publish a
(cid:145)2.
report on the experience acquired on the basis of
the
procedures described in this Chapter and shall propose
any amendments which may be necessary to improve
those procedures.(cid:146)

29. Article 39 is replaced by the following:

(cid:145)Article 39

The provisions of Article 29(3), (4) and (5) and of Articles
30 to 34 shall not apply to the homeopathic medicinal
products referred to in Article 14.

The provisions of Articles 28 to 34 shall not apply to the
homeopathic medicinal products referred to in Article
16(2).(cid:146)

30. The following paragraph 4 is added to Article 40:

(cid:145)4.
The Member States shall forward to the Agency a
copy of the authorisation referred to in paragraph 1. The
Agency shall enter that information on the database.(cid:146)

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31. In Article 46, point (f) is replaced by the following:

products in accordance with the requirements of the
marketing authorisation.(cid:146)

(cid:145)(f)

to comply with the principles and guidelines of good
manufacturing practice for medicinal products and, in
so doing, to use only active substances employed as
starting materials which have been manufactured in
accordance with the detailed guidelines on good manu-
facturing practice for starting materials.(cid:146)

32. A new Article 46a is inserted:

(cid:145)Article 46a

For the purpose of

this Directive, manufacture of
1.
include
active substances used as starting materials shall
import of an
both total and partial manufacture or
active substance used as a starting material as defined in
the second part of Section C of Annex I, and the various
processes of dividing up, packaging or presentation prior
to its incorporation into a medicinal product,
including
repackaging or re-labelling, such as are carried out by a
distributor of starting materials.

Any amendments necessary to adapt paragraph 1 to
2.
new scientific and technical developments shall be laid
down in accordance with the procedure referred to in
Article 121(2).(cid:146)

37. Article 54 is amended as follows:

(a) Point (a) is replaced by the following:

(cid:145)(a)

the name of the medicinal product followed by its
strength and pharmaceutical form (baby, child or
adult as appropriate); the common name shall be
included where the product contains only one
active substance and if its name is an invented
name;(cid:146)

(b) In point
guidance(cid:146).

(d),

(cid:145)guidelines(cid:146)

is

replaced by (cid:145)detailed

(c) Point (f) is replaced by the following:

(cid:145)(f) a special warning that the medicinal product must
be stored out of the reach and sight of children;(cid:146)

(d) Point (k) is replaced by the following:

(cid:145)(k) the name and address of the marketing author-
isation holder and, where applicable, the name of
the representative appointed by the holder
to
represent him/her;(cid:146)

33. In Article 47, the following third and fourth paragraphs are

(e) Point (n) is replaced by the following:

added:

(cid:145)The principles of good manufacturing practice for active
substances used as starting materials referred to in point (f)
of Article 46 shall be adopted in the form of detailed
guidelines.

The Commission shall also publish guidelines on the
format and content of
the authorisation referred to in
Article 40(1), on the reports referred to in Article 111(3)
and on the format and content of the certificate of good
manufacturing practice referred to in Article 111(5).(cid:146)

34. In Article 49(1), (cid:145)minimum(cid:146) is deleted.

35. In Article 50(1),

(cid:145)in the State concerned(cid:146)

is replaced by

(cid:145)within the Community(cid:146).

36. In Article 51(1), point (b) is replaced by the following:

(cid:145)(n) in the case of non-prescription medicinal products,

instructions for use.(cid:146)

38. Article 55 is amended as follows:

(a)

In paragraph 1, (cid:145)in Articles 54 and 62(cid:146) is replaced by
(cid:145)in Article 54(cid:146);

(b) The first
following:

indent of paragraph 2 is replaced by the

(cid:145)(cid:151) the name of the medicinal product as laid down in

point (a) of Article 54,(cid:146)

(c) The first
following:

indent of paragraph 3 is replaced by the

(cid:145)(cid:151) the name of the medicinal product as laid down in
point (a) of Article 54 and, if necessary, the route
of administration,(cid:146)

(cid:145)(b)

in the case of medicinal products coming from third
irrespective of whether the product has
countries,
been manufactured in the Community,
that each
production batch has undergone in a Member State
a full qualitative analysis, a quantitative analysis of at
least all the active constituents and all the other tests
or checks necessary to ensure the quality of medicinal

39. In Article 57, the following second paragraph is added:

(cid:145)For medicinal products authorised under the provisions of
Regulation [(EEC) No 2309/93], Member States shall, when
applying this Article, observe
the detailed guidance
referred to in Article 65 of this Directive.(cid:146)

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40. Article 59 is replaced by the following:

(cid:145)Article 59

The package leaflet shall be drawn up in accordance
1.
with the summary of the product characteristics; it shall
include, in the following order:

(a)

for the identification of the medicinal product:

(i) the name of the medicinal product followed by its
strength and pharmaceutical form (baby, child or
adult as appropriate). The common name shall be
included where the product contains only one
active substance and if
its name is an invented
name;

(ii) the pharmaco-therapeutic group or type of activity
in terms easily comprehensible for the patient;

(b) the therapeutic indications;

(c) a list of information which is necessary before taking

the medicinal product:

(i) contra-indications;

(ii) appropriate precautions for use;

(iii) forms of interaction with other medicinal products
and other
interaction (e.g. alcohol,
tobacco, foodstuffs) which may affect the action
of the medicinal product;

forms of

(iv) special warnings;

(d) a description of the adverse reactions which may occur
under normal use of the medicinal product and,
if
necessary, the action to be taken in such a case; the
patient should be expressly asked to communicate any
adverse reaction which is not mentioned in the
package leaflet to his doctor or pharmacist;

(e)

the necessary and usual
and in particular:

instructions for proper use,

(i) the dosage,

(ii) the method and,

if necessary, route of adminis-

tration;

(iii) the frequency of administration,

if
necessary,
the appropriate time at which the
medicinal product may or must be administered;

specifying,

and, as appropriate, depending on the nature of the
product:

(v) the action to be taken in the case of an overdose
(such as symptoms, emergency procedures);

(vi) what to do when one or more doses have not

been taken;

(vii) indication, if necessary, of the risk of withdrawal

effects;

(f) a reference to the expiry date indicated on the label,

with:

(i) a warning against using the product after this date;

(ii) where appropriate, special storage precautions;

(iii) if necessary, a warning against certain visible signs

of deterioration;

(iv) the

full

qualitative

composition

active
substances and excipients) and the quantitative
composition in active substances, using common
names,
the medicinal
product;

for each presentation of

(in

(v) for each presentation of the product, the phar-
maceutical form and content in weight, volume
or units of dosage;

(vi) the name and address of the marketing author-
isation holder and, where applicable, the name of
in the Member
his appointed representatives
States;

(g) where the medicinal product is authorised according to
the procedure provided for in Articles 28 to 39 under
different names in the Member States concerned, a list
of the names authorised in each Member State;

(h) the date on which the package leaflet was last revised.

2.

The list set out in point (c) of paragraph 1 shall:

(a) take into account the particular condition of certain
categories of users (children, pregnant or breastfeeding
women, the elderly, persons with specific pathological
conditions);

(iv) the duration of

treatment, where it should be

(b) mention, if appropriate, possible effects on the ability

limited;

to drive vehicles or to operate machinery;

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(c)

list those excipients knowledge of which is important
for the safe and effective use of the medicinal product
and which are included in the detailed guidance
published pursuant to Article 65.(cid:146)

45. Article 69(1) is amended as follows:

(a) The first indent is replaced by the following:

41. In Article 61(4),

(cid:145)or as appropriate(cid:146)

is replaced by (cid:145)and(cid:146).

42. In Article 62, (cid:145)for health education(cid:146) is replaced by (cid:145)for the

patient(cid:146).

43. Article 63 is amended as follows:

(a) The

following

third

subparagraph is

added

to

paragraph 1:

(cid:145)In the case of certain orphan medicinal products, the
particulars
listed in Article 54 may, on reasoned
request, appear in one of the official languages of the
Community.(cid:146)

(b) Paragraph 3 is replaced by the following:

(cid:145)3. When the product is not intended to be delivered
directly to the patient, the competent authorities may
grant an exemption to the obligation that certain
particulars should appear on the labelling and in the
package leaflet and that the leaflet must be in the
official
the Member State
language or languages of
where the product is placed on the market.(cid:146)

44. Article 65 is replaced by the following:

(cid:145)Article 65

In consultation with the Member States and the parties
the Commission shall draw up and publish
concerned,
detailed guidance concerning in particular:

(a) the wording of certain special warnings for certain

categories of medicinal products;

(cid:145)(cid:151) the scientific name of the stock or stocks followed
by the degree of dilution, making use of
the
symbols of the pharmacopoeia used in accordance
with Article 1(5);
if the homeopathic medicinal
product is composed of two or more stocks, the
scientific names of the stocks on the labelling may
be replaced by an invented name(cid:146)

(b) The twelfth indent is replaced by the following:

(cid:145)(cid:151) a warning advising the user to consult a doctor if

the symptoms persist(cid:146)

46. Article 70(2) is amended as follows:

(a) Point (a) is replaced by the following:

(cid:145)(a) medicinal products on medical prescription for

renewable or non-renewable delivery;(cid:146)

(b) Point (c) is replaced by the following:

(cid:145)(c) medicinal

products

(cid:147)restricted(cid:148) medical
on
prescription, reserved for use in certain specialised
areas.(cid:146)

47. Article 74 is replaced by the following:

(cid:145)Article 74

the
When new facts are brought
competent authorities shall examine and, as appropriate,
amend the classification of a medicinal product by
applying the criteria listed in Article 71.(cid:146)

to their attention,

48. The heading of Title VII is replaced by the following:

(b) the particular information needs relating to self-medi-

cation;

(cid:145)TITLE VII

(c)

the legibility of particulars on the labelling and package
leaflet;

Distribution of medicinal products(cid:146)

49. Article 76 is amended as follows:

(d) the methods for the identification and authentication

(a) The existing text becomes paragraph 1.

of medicinal products;

(e)

the list of excipients which must
feature on the
labelling of medicinal products and the way in which
these excipients must be indicated;

(f) harmonised provisions

for

the implementation of

Article 57.(cid:146)

(b) The following new paragraph 2 is inserted:

(cid:145)2.
In the case of wholesale distribution and storage,
medicinal products shall be covered by a marketing
authorisation issued pursuant
to [Regulation (EEC)
No 2309/93] or by the competent authorities of a
Member State in accordance with this Directive.(cid:146)

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50. The second indent of point (e) of Article 80 is replaced by

the following:

to product
legitimate needs. This provision applies
information appended to the marketing authorisation as
well as to additional related information.

(cid:145)(cid:151) name of the medicinal product,(cid:146)

51. In Article 82, the second indent of the first paragraph is

replaced by the following:

(cid:145)(cid:151) the name and pharmaceutical form of the medicinal

product,(cid:146)

52. Article 84 is replaced by the following:

(cid:145)Article 84

The Commission shall publish guidelines on good
the
distribution practice. To this end,
Committee and the Pharmaceutical Committee established
by Council Decision 75/320/EEC (*).
___________
(*) OJ L 147, 9.6.1975, p. 23.(cid:146)

it shall consult

By way of derogation from the prohibition in paragraph
1(a), Member States shall authorise the dissemination of
information relating to certain medicinal products auth-
orised in the framework of the affections set out below,
in order to respond to the expectations expressed by the
patients’ groups:

This dissemination of information shall be carried out on
the following conditions:

(a) the medicinal product

authorised and
prescribed for the treatment of any of the following
conditions:

shall be

(cid:151) acquired immune deficiency syndrome;

(cid:151) asthma and chronic broncopulmonary disorders;

53. Article 86 is amended as follows:

(cid:151) diabetes;

(a)

In paragraph 1, the introductory phrase is replaced by
the following:

(b) the information disseminated complies with the prin-

ciples set out in this Title;

shall

(cid:145)For the purposes of this Title, (cid:147)advertising of medicinal
include any form of door-to-door
products(cid:148)
information,
inducement
designed to promote the prescription, supply, sale,
consumption or
availability of
medicinal products; it shall include in particular:(cid:146)

awareness of

canvassing

activity

the

or

(b) The fourth indent of the paragraph 2 is replaced by the

following:

(cid:145)(cid:151) information relating to human health or diseases,
provided that there is no reference, even indirect,
to medicinal products, and without prejudice to
Article 88(2) of this Directive.(cid:146)

54. Article 88 is replaced by the following:

(cid:145)Article 88

1. Member States shall prohibit the advertising to the
general public of medicinal products which:

(a) are

available on medical prescription only,

in

accordance with Title VI;

(b) contain substances defined as psychotropic or narcotic
the United
convention,

by international
such as
Nations Conventions of 1961 and 1971.

The

communication of

2.
information on certain
medicinal products is authorised under strict conditions
in the interest of patients in order to respond to their

(c)

implementation of this paragraph shall be conditioned
by the setting-up of self-regulatory procedures by the
pharmaceutical industry at Member State level;

(d) the information and its dissemination shall be in
conformity with the principles of good practice
which are adopted, after consultation with interested
parties,
in conformity with the procedure set out in
Article 121(2).

(e)

in order to monitor the implementation of the prin-
ciples of good practice referred to above:

(cid:151) the additional information related to the medicinal
the
products shall be notified to the Agency.
Agency does not object within 30 days following
this notification, the information shall be deemed
to be accepted;

If

(cid:151) the Agency shall coordinate the monitoring of the
information on the medicinal products authorised
in conformity with this Directive,
in particular
through the setting-up of a data base;

(cid:151) on a yearly basis, the Agency shall prepare a report
these principles of good

on the application of
practice;

(f)

implementation of this paragraph shall be the subject
of an evaluation and a detailed report no later than
[date]. The Commission shall propose any changes
required to improve its implementation.

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3. Medicinal products may be advertised to the general
public which, by virtue of their composition and purpose,
are intended and designed for use without the intervention
of a medical practitioner for diagnostic purposes or for the
prescription or monitoring of treatment, with the advice of
the pharmacist, if necessary.

4. Member States shall be able to ban, on their territory,
advertising to the general public of medicinal products, the
cost of which may be reimbursed.

5.
The prohibition contained in paragraph 1 shall not
apply to vaccination campaigns carried out by the industry
and approved by the competent authorities of the Member
States.

The prohibition referred to in paragraph 1 shall
to Article 14 of Directive

6.
apply without prejudice
89/552/EEC.

7. Member States shall prohibit the direct distribution of
medicinal products to the public by the industry for
promotional purposes.(cid:146)

55. Article 89 is amended as follows:

58. Point (d) of Article 96(1) is replaced by the following:

(cid:145)(d) each sample shall be no larger than the smallest pres-

entation on the market,(cid:146)

59. In Article 98, the following paragraph 3 is added:

The Member States shall authorise the co-promotion
(cid:145)3.
of a medicinal product by the holder of the marketing
authorisation and one or more companies nominated by
him/her.(cid:146)

60. Article 100 is replaced by the following:

(cid:145)Article 100

the homeopathic medicinal products
Advertising of
referred to in Article 14(1)
to the
provisions of this Title with the exception of Article 87(1).

shall be subject

However, only the information specified in Article 69(1)
may be used in the advertising of such medicinal products.(cid:146)

61. In Article 101, the second paragraph is replaced by the

(a) the first indent of point (b) of paragraph 1 is replaced

following:

by the following:

(cid:145)(cid:151) the name of the medicinal product, as well as the
common name if the medicinal product contains
only one active substance,(cid:146)

(cid:145)The Member States may impose specific requirements on
doctors and other health care professionals in respect of
the reporting of suspected serious or unexpected adverse
reactions.(cid:146)

(b) paragraph 2 is replaced by the following:

62. Article 102 is replaced by the following:

(cid:145)2. Member States may decide that the advertising of
a medicinal product to the general public may, by way
of derogation from paragraph 1, include only the name
of the medicinal product if it is intended solely as a
reminder.(cid:146)

56. Article 90 is amended as follows:

(a) Point (c) is replaced by the following:

(cid:145)(c) suggests that the subject’s state of health can be
immediately improved by taking the medicinal
product;(cid:146)

(b) In point (d), (cid:145)Article 88(4)(cid:146) is replaced by (cid:145)Article 88(5)(cid:146).

(c) Point l is deleted.

57.

In Article 91, paragraph 2 is replaced by the following:

(cid:145)2. Member States may decide that the advertising of a
medicinal product
to persons qualified to prescribe or
supply such products may, notwithstanding paragraph 1,
include only the name of the medicinal product, if it is
intended solely as a reminder.(cid:146)

(cid:145)Article 102

decisions

regulatory

concerning

In order
to ensure the adoption of appropriate and
the
harmonised
medicinal products authorised within the Community,
having regard to information obtained about adverse
reactions to medicinal products under normal conditions
a phar-
of use,
macovigilance system. This
system shall be used to
collect information useful in the surveillance of medicinal
products, with particular reference to adverse reactions in
human beings, and to evaluate such information scien-
tifically.

the Member States

shall operate

shall ensure that

suitable information
Member States
collected within this
system is communicated to the
other Member States and the Agency. The information
shall be recorded in the database referred to in point (j)
of the second paragraph of Article 51 of Regulation (EEC)
No 2309/93 and shall be permanently accessible to all
Member States.

This system shall also take into account any available
information on misuse and abuse of medicinal products
which may have an impact on the evaluation of
their
benefits and risks.(cid:146)

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63. In Article 103,

the introductory phrase of

the second

paragraph is replaced by the following:

authority acting as reference Member State. The reference
Member State shall assume the responsibility of analysing
and monitoring such adverse reactions.

(cid:145)That qualified person shall reside in the Community and
shall be responsible for the following:(cid:146)

64. Articles 104 to 107 are amended as follows:

(cid:145)Article 104

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

Save in exceptional circumstances, these reactions shall be
communicated electronically in the form of a report
according to the guidelines referred to in Article 106(1).

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

territory the

3.
The marketing authorisation holder shall be required
to record and report all other suspected serious adverse
reactions which meet
in
the
referred to in Article
accordance with the guidelines
106(1), 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.

notification

criteria

4.
The marketing authorisation holder shall ensure that
all suspected serious and unexpected adverse reactions
occurring in the territory of a third country are reported
immediately in accordance with the guidelines referred to
in Article 106(1), so that the Agency and the competent
authorities of
the Member States where the medicinal
product is authorised are informed of them, and in no
case later than 15 calendar days following the receipt of
the information.

By way of derogation from paragraphs 2, 3 and 4, in
5.
the case of medicinal products which are covered by
the
Directive 87/22/EEC or which have qualified for
procedures laid down in Articles 28 and 29 of
this
Directive or which have been the subject of the procedures
under Articles 32, 33 and 34 of
the
marketing authorisation holder shall also ensure that all
suspected serious adverse reactions occurring in the
Community are reported in such a way as to be accessible
to any competent
to the reference Member State or

this Directive,

6.
Unless other requirements have been laid down as a
condition of the granting of authorisation, or subsequently
as indicated in the guidelines referred to in Article 106(1),
reports 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 period-
ically as follows: six monthly for the first two years after
authorisation, annually for the subsequent two years, and
three-yearly intervals. The periodic safety
thereafter at
update reports shall include a scientific evaluation of the
benefits and risks of the medicinal product.

Following the granting of a marketing authorisation,
7.
the
the marketing authorisation holder may request
amendment of
the periods referred to in paragraph 6
according to the procedure laid down by Commission
Regulation (EC) No 541/95 (*).
___________
(*) OJ L 55, 11.3.1995, p. 7.

Article 105

The Agency, in collaboration with the Member States
1.
and the Commission,
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.

shall

2. Making use of the network referred to in paragraph
1, 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
days of their notification at the latest.

The Member States shall ensure that

reports of
3.
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
days of their notification at the latest.

Article 106

the

within

Community,

In order to facilitate the exchange of information on
1.
the
pharmacovigilance
Commission, after consulting the Agency,
the Member
States and interested parties, shall draw up guidelines on
the collection, verification and presentation of adverse
reaction reports, including technical requirements for elec-
tronic exchange of pharmacovigilance information in
accordance with internationally agreed formats, and shall
publish a reference to an internationally agreed medical
terminology.

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Acting in accordance with the guidelines, marketing auth-
orisation holders shall use internationally agreed medical
terminology for the reporting of adverse reactions.

inspections,
medicinal products are complied with.

the legal

that

requirements governing

governing Medicinal

These guidelines shall be published in Volume 9 of The
Rules
European
Community and shall take account of international harmon-
isation work carried out in the field of pharmacovigilance.

Products

the

in

2.
For the interpretation of the definitions referred to in
points 11 to 16 of Article 1 and of the principles outlined
in this Title, the marketing authorisation holder and the
competent authorities shall follow the guidelines referred
to in paragraph 1.

Article 107

the evaluation of phar-
1. Where, as a result of
macovigilance data, a Member State considers
that a
marketing authorisation should be suspended, withdrawn
or varied in accordance with the guidelines referred to in
Article 106(1), it shall forthwith inform the Agency, the
other Member States and the marketing authorisation
holder.

2. Where urgent action to protect public health is
necessary, the Member State concerned may suspend the
marketing authorisation of a medicinal product, provided
that the Agency, the Commission and the other Member
States are informed no later than the following working
day.

informed in accordance with
When the Agency is
paragraph 1 or the first subparagraph of this paragraph,
the Committee shall prepare an opinion within a time
frame to be determined depending on the urgency of the
matter.

Acting on the basis of this opinion, the Commission may
request all Member States where the product
is being
marketed to take temporary measures immediately.

The final measures shall be adopted in accordance with the
procedure described in Article 121(3), where the draft
decision is in accordance with the Agency’s opinion.

The final measures shall be adopted in accordance with the
procedure described in Article 121(4), where the draft
decision is not in accordance with the Agency’s opinion.(cid:146)

65. Article 111 is amended as follows:

(a) Paragraph 1 is replaced by the following:

(cid:145)1.
concerned

The competent authority of the Member State
repeated

ensure, by means of

shall

there

The competent authority may carry out inspections at
the premises of manufacturers of active substances
used as starting materials, or of
the premises of
marketing authorisation holders whenever it considers
that
suspecting
non-compliance with the principles and guidelines of
good management practice referred to in Article 47.
These inspections may also be carried out at
the
request of a Member State, the Commission or the
Agency.

grounds

serious

are

for

In order to verify whether the data submitted in order
to obtain a conformity certificate comply with the
monographs of the European Pharmacopoeia, the stan-
dardisation body of the nomenclatures and the quality
norms within the meaning of the Convention relating
to the elaboration of the European Pharmacopoeia (*)
(European Directorate for
the quality of Medicinal
Products) may ask the Commission or the Agency to
request such an inspection when the starting material
concerned is the subject of a European Pharmacopoeia
monograph.

competent

authority of

State
The
concerned may carry out
starting
material manufacturers at the specific request of the
manufacturer himself.

inspections of

the Member

Such inspections shall be carried out by officials repre-
senting
authority who shall be
empowered to:

competent

the

(a)

inspect
the manufacturing or commercial estab-
lishments of manufacturers of medicinal products
or of active substances used as starting materials,
and any laboratories employed by the holder of the
manufacturing authorisation to carry out checks
pursuant to Article 20;

(b) take samples;

(c) examine any documents relating to the object of
the inspection, subject to the provisions in force in
the Member States on 21 May 1975 placing
restrictions on these powers with regard to the
descriptions of the method of preparation;

(d) inspect

the premises of marketing authorisation
holders or any firms employed by the marketing
authorisation holder
to perform the activities
described in Title IX, and in particular Articles
103 and 104.

___________
(*) OJ L 158, 25.6.1994, p. 19.(cid:146)

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(b) Paragraph 3 is replaced by the following:

(cid:145)3.
After every inspection as referred to in paragraph
1, the officials representing the competent authority
shall report on whether the manufacturer complies
with the principles and guidelines of good manufac-
turing practice laid down in Article 47 or, where
appropriate, with the requirements
laid down in
Articles 101 to 108. The content of such reports
shall be
communicated to the manufacturer or
marketing authorisation holder who has undergone
the inspection.(cid:146)

(c) The following paragraphs 4 to 7 are added:

(cid:145)4. Without prejudice to any arrangements which
may have been concluded between the Community
and third countries, a Member State, the Commission
or the Agency may require a manufacturer established
in a third country to submit
to an inspection as
referred to in paragraph 1.

5. Within 90 days of an inspection as referred to in
paragraph 1, a certificate of good manufacturing
practice shall be issued to a manufacturer
the
outcome of the inspection shows that the manufacturer
complies with the principles and guidelines of good
manufacturing
by
Community legislation.

provided

practice

for

as

if

If inspections are performed as part of the certification
procedure for the monographs of the European Phar-
macopoeia, a certificate shall be drawn up.

6. Member States shall enter the certificates of good
manufacturing practice which they
in a
Community register managed by the Agency on
behalf of the Community.

issue

7.
If the outcome of the inspection as referred to in
paragraph 1 is that the manufacturer does not comply
with the principles and guidelines of good manufac-
turing practice as provided for by Community legis-
lation,
entered in the
information shall be
Community register as referred to in paragraph 6.(cid:146)

the

66. Article 116 is replaced by the following:

(cid:145)Article 116

The competent authorities shall suspend or revoke an
authorisation to place a medicinal product on the market
if the view is taken that the product is harmful under
normal conditions of use, or that
lacks therapeutic
efficacy, or that the risk-benefit balance is not positive
under the authorised conditions of use, or that its quali-
tative and quantitative composition is not as declared.
Therapeutic efficacy is lacking when it is concluded that
therapeutic results cannot be obtained from the medicinal
product.

it

An authorisation shall also be suspended or revoked where
the particulars supporting the application as provided for
in Article 8 or Articles 10 to 11 are incorrect or have not
been amended in accordance with Article 23, or where the
controls referred to in Article 112 have not been carried
out.(cid:146)

67. Article 117(1) is replaced by the following:

(cid:145)1. Without prejudice to the measures provided for in
Article 116, Member States shall take all appropriate steps
to ensure that
is
prohibited and the medicinal product withdrawn from
the market, if the view is taken that:

the medicinal product

the supply of

(a) the medicinal product
conditions of use; or

is harmful under normal

(b) it lacks therapeutic efficacy; or

(c)

the risk-benefit balance is not favourable under the
authorised conditions of use; or

(d) its qualitative and quantitative composition is not as

declared; or

(e)

the controls on the medicinal product and/or on the
ingredients and the controls at an intermediate stage of
the manufacturing process have not been carried out
or if some other requirement or obligation relating to
the grant of the manufacturing authorisation has not
been fulfilled.(cid:146)

68. Article 119 is replaced by the following:

(cid:145)Article 119

The provisions of this Title shall apply to homeopathic
medicinal products.(cid:146)

69. Articles 121 and 122 are replaced by the following:

(cid:145)Article 121

1.
The Commission shall be assisted by the Standing
Committee on Medicinal Products for Human Use, here-
in the task of
inafter called (cid:147)the Standing Committee(cid:148),
adapting to technical progress
the directives on the
removal of technical barriers to trade in the medicinal
products
shall be
sector. The
the Member States and
composed of representatives of
chaired by a representative of the Commission.

Standing Committee

2. Where reference is made to this paragraph, the regu-
latory procedure laid down in Article 5 of Decision
in compliance with Articles 7
1999/468/EC shall apply,
and 8 thereof.

The period provided for
1999/468/EC shall be three months.

in Article 5(6) of Decision

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the
3. Where reference is made to this paragraph,
advisory procedure laid down in Article 3 of Decision
1999/468/EC shall apply,
in compliance with Articles 7
and 8 thereof.

4. Where reference is made to this paragraph,
management procedure
Decision 1999/468/EC shall apply,
Articles 7 and 8 thereof.

the
laid down in Article 4 of
in compliance with

The period provided for
1999/468/EC shall be one month.

in Article 4(3) of Decision

The Standing Committee shall adopt its own rules of

5.
procedure.

Article 122

the

that

competent

1. Member States shall take all appropriate measures to
ensure
concerned
communicate to each other such information as is appro-
priate to guarantee that the requirements placed on the
authorisations referred to in Article 40, on the certificates
referred to in Article 111(5) or on the marketing author-
isations are fulfilled.

authorities

Upon

reasoned

2.
shall
forthwith communicate the reports referred to in Article
111(3) to the competent authorities of another Member
State.

request, Member

States

However, in exceptional cases, if a Member State is unable,
relating to public health,
for
the
reasons
conclusions
an inspection under
following
reached
Article 111(1), that Member State shall forthwith inform
the Commission and the Agency

to accept

When the Commission is informed of these difficulties, it
may, after consulting the Member States concerned, ask the
inspector who performed the original
inspection to
perform a new inspection; the inspector may be accom-
panied by two other inspectors from Member States who
are not parties to the disagreement.(cid:146)

Article 2

Member States shall bring into force the laws, regulations and
administrative provisions necessary to comply with this
Directive no later than [date]. They shall immediately inform
the Commission thereof.

When Member States adopt those provisions, they shall contain
a reference to this Directive or be accompanied by such a
their official publication.
reference on the occasion of
Member States shall determine how such reference is to be
made.

Article 3

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

The conclusions

3.
reached following an inspection
under Article 111(1) which is carried out by the inspec-
torate of
the Member State concerned shall be valid
throughout the Community.

Article 4

This Directive is addressed to the Member States.