Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products
Date: 1999-12-16
Institutions: Council of the European Union, European Parliament
Subjects: European Medicines Agency, disease prevention, drugs classification, market approval, medical diagnosis, medicinal product, scientific research

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I

(Acts whose publication is obligatory)

REGULATION (EC) No 141/2000 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL

of 16 December 1999

on orphan medicinal products

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE
EUROPEAN UNION,

tions of competition and barriers to intra-Community
trade;

(4)

(5)

(6)

(7)

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

Having regard to the proposal from the Commission (1),

Having regard to the opinion of the Economic and Social
Committee (2),

Acting in accordance with the procedure laid down in Article
251 of the Treaty (3),

Whereas:

(1)

(2)

(3)

to diagnose, prevent or treat

some conditions occur so infrequently that the cost of
developing and bringing to the market a medicinal
product
the condition
would not be recovered by the expected sales of the
medicinal product; the pharmaceutical
industry would
be unwilling to develop the medicinal product under
normal market conditions; these medicinal products are
called ‘orphan’;

patients suffering from rare conditions should be enti-
tled to the same quality of treatment as other patients; it
is therefore necessary to stimulate the research, develop-
ment and bringing to the market of appropriate medica-
tions by the pharmaceutical industry; incentives for the
development of orphan medicinal products have been
available in the United States of America since 1983 and
in Japan since 1993;

in the European Union, only limited action has been
taken so far, whether at national or at Community level,
to stimulate the development of orphan medicinal prod-
ucts; such action is best taken at Community level in
order to take advantage of the widest possible market
and to avoid the dispersion of limited resources; action
at Community level is preferable to uncoordinated meas-
ures by the Member States which may result in distor-

(1) OJ C 276, 4.9.1998, p. 7.
(2) OJ C 101, 12.4.1999, p. 37.
(3) Opinion of the European Parliament of 9 March 1999 (OJ C 175,
21.6.1999, p. 61), Council Common Position of 27 September
1999 (OJ C 317, 4.11.1999, p. 34) and Decision of the European
Parliament of 15 December 1999 (not yet published in the Official
Journal).

orphan medicinal products eligible for incentives should
be easily and unequivocally identified;
it seems most
appropriate to achieve this result through the establish-
ment of an open and transparent Community procedure
for the designation of potential medicinal products as
orphan medicinal products;

objective criteria for designation should be established;
those criteria should be based on the prevalence of the
condition for which diagnosis, prevention or treatment
is sought; a prevalence of not more than five affected
persons per 10 thousand is generally regarded as the
appropriate threshold; medicinal products intended for a
life-threatening, seriously debilitating or serious and
chronic condition should be eligible even when the
prevalence is higher than five per 10 thousand;

for designation;

a Committee composed of experts appointed by the
Member States should be established to examine applica-
tions
this Committee should also
include three representatives of patients' associations,
designated by the Commission, and three other persons,
also designated by the Commission, on a recommenda-
tion from the European Agency for the Evaluation of
Medicinal Products
‘the
(hereinafter
Agency’);
the Agency should be responsible for the
adequate coordination between the Committee on
orphan medicinal products and the Committee on
proprietary medicinal products;

referred to as

patients with such conditions deserve the same quality,
safety and efficacy in medicinal products as other
patients; orphan medicinal products should therefore be
submitted to the normal evaluation process; sponsors of
orphan medicinal products should have the possibility
in order to
of obtaining a Community authorisation;
facilitate
a
Community authorisation, fees to be paid to the Agency
should be waived at least in part; the Community budget
should compensate the Agency for the loss in revenue
thus occasioned;

the maintenance of

the granting or

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(8)

(9)

(10)

(11)

experience in the United States of America and Japan
shows that the strongest incentive for industry to invest
in the development and marketing of orphan medicinal
products is where there is a prospect of obtaining
market exclusivity for a certain number of years during
which part of the investment might be recovered; data
protection under Article 4(8)(a)(iii) of Council Directive
65/65/EEC of 26 January 1965 on the approximation of
provisions laid down by law, regulation or adminis-
trative action relating to medicinal products (1) is not a
incentive for that purpose; Member States
sufficient
acting independently cannot introduce such a measure
without a Community dimension as such a provision
would be contradictory to Directive 65/65/EEC; if such
measures were adopted in an uncoordinated manner by
the Member States, this would create obstacles to intra-
Community trade, leading to distortions of competition
and running counter to the single market; market exclu-
sivity should however be limited to the therapeutic indi-
cation for which orphan medicinal product designation
has been obtained, without prejudice to existing intellec-
tual property rights;
the
market exclusivity granted to an orphan medicinal
product should not prevent the marketing of a similar
medicinal product which could be of significant benefit
to those affected by the condition;

in the interest of patients,

sponsors of orphan medicinal products designated under
this Regulation should be entitled to the full benefit of
any incentives granted by the Community or by the
Member States to support the research and development
of medicinal products for the diagnosis, prevention or
including rare diseases;
treatment of such conditions,

the specific programme Biomed 2, of the fourth frame-
work programme for research and technological devel-
opment
(1994 to 1998), supported research on the
treatment of rare diseases, including methodologies for
rapid schemes for the development of orphan medicinal
products and inventories of available orphan medicinal
products in Europe;
those grants were intended to
promote the establishment of cross national cooperation
in order to implement basic and clinical research on rare
diseases; research on rare diseases continues to be a
priority for the Community, as it has been included in
the fifth framework programme for research and techno-
logical development (1998 to 2002); this Regulation
establishes a legal framework which will allow the swift
and effective implementation of the outcome of this
research;

rare diseases have been identified as a priority area for
Community action within the framework for action in
in its
the field of public health;
communication
of
concerning
Community action on rare diseases within the frame-
work for action in the field of public health has decided
to give rare diseases priority within the public health

the Commission,

programme

a

framework; the European Parliament and the Council
have adopted Decision No 1295/1999/EC of 29 April
1999 adopting a programme of Community action on
rare diseases within the framework for action in the field
of public health (1999 to 2003) (2), including actions to
rare
provide information,
diseases in a population and to support relevant patient
organisations; this Regulation implements one of the
priorities laid down in this programme of action,

to deal with clusters of

HAVE ADOPTED THIS REGULATION:

Article 1

Purpose

The purpose of this Regulation is to lay down a Community
procedure for the designation of medicinal products as orphan
medicinal products and to provide incentives for the research,
development and placing on the market of designated orphan
medicinal products.

Article 2

Definitions

For the purposes of this Regulation:

(a) ‘medicinal product’ means a medicinal product for human
use, as defined in Article 2 of Directive 65/65/EEC;

(b) ‘orphan medicinal product’ means a medicinal product
designated as such under the terms and conditions of this
Regulation;

(c) ‘sponsor’ means any legal or natural person, established in
the Community, seeking to obtain or having obtained the
designation of a medicinal product as an orphan medicinal
product;

(d) ‘Agency’ means the European Agency for the Evaluation of

Medicinal Products.

Article 3

Criteria for designation

A medicinal product shall be designated as an orphan

1.
medicinal product if its sponsor can establish:

(a) that it is intended for the diagnosis, prevention or treat-
ment of a life-threatening or chronically debilitating condi-
tion affecting not more than five in 10 thousand persons in
the Community when the application is made, or

that it is intended for the diagnosis, prevention or treat-
ment of a life-threatening, seriously debilitating or serious
and chronic condition in the Community and that without
incentives it is unlikely that the marketing of the medicinal
product in the Community would generate sufficient return
to justify the necessary investment;

(1) OJ 22, 9.2.1965, p. 369. Directive as last amended by Directive

93/39/EEC (OJ L 214, 24.8.1993, p. 22).

(2) OJ L 155, 22.6.1999, p. 1.

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and

(b) that

there exists no satisfactory method of diagnosis,
prevention or treatment of the condition in question that
has been authorised in the Community or, if such method
exists, that the medicinal product will be of significant
benefit to those affected by that condition.

2.
The Commission shall adopt the necessary provisions for
implementing this Article in the form of an implementing
Regulation in accordance with the procedure laid down in
Article 72 of Council Regulation (EEC) No 2309/93 (1).

Article 4

Committee for Orphan Medicinal Products

A Committee for Orphan Medicinal Products, hereinafter
is hereby set up within the

1.
referred to as ‘the Committee’,
Agency.

2.

The task of the Committee shall be:

(a) to examine any application for the designation of a medi-
cinal product as an orphan medicinal product which is
submitted to it in accordance with this Regulation;

(b) to advise the Commission on the establishment and devel-
opment of a policy on orphan medicinal products for the
European Union;

(c) to assist

the Commission in liaising internationally on
matters relating to orphan medicinal products, and in
liaising with patient support groups;

(d) to assist the Commission in drawing up detailed guidelines.

The Committee shall consist of one member nominated
3.
by each Member State,
three members nominated by the
Commission to represent patients' organisations and three
members nominated by the Commission on the basis of a
recommendation from the Agency. The members of
the
Committee shall be appointed for a term of three years, which
shall be renewable. They may be accompanied by experts.

The Committee shall elect its Chairman for a term of

4.
three years, renewable once.

5.
The representatives of the Commission and the Executive
Director of the Agency or his representative may attend all
meetings of the Committee.

The Agency

6.
Committee.

shall provide

the

secretariat of

the

7. Members of the Committee shall be required, even after
their duties have ceased, not to disclose any information of the
kind covered by the obligation of professional secrecy.

Article 5

Procedure for designation and removal from the register

In order to obtain the designation of a medicinal product
1.
as an orphan medicinal product, the sponsor shall submit an
application to the Agency at any stage of the development of

(1) OJ L 214, 24.8.1993, p. 1. Regulation as amended by Commission

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

the medicinal product before the application for marketing
authorisation is made.

The application shall be accompanied by the following

2.
particulars and documents:

(a) name or corporate name and permanent address of the

sponsor;

(b) active ingredients of the medicinal product;

(c) proposed therapeutic indication;

(d) justification that the criteria laid down in Article 3(1) are
the stage of development,

met and a description of
including the indications expected.

3.
The Commission shall, in consultation with the Member
States, the Agency and interested parties, draw up detailed
guidelines on the required format and content of applications
for designation.

4.
The Agency shall verify the validity of the application and
prepare a summary report to the Committee. Where appro-
priate, it may request the sponsor to supplement the particulars
and documents accompanying the application.

5.
The Agency shall ensure that an opinion is given by the
Committee within 90 days of the receipt of a valid application.

6. When preparing its opinion, the Committee shall use its
best endeavours to reach a consensus. If such a consensus
cannot be reached, the opinion shall be adopted by a majority
of two-thirds of the members of the Committee. The opinion
may be obtained by written procedure.

7. Where the opinion of the Committee is that the applica-
tion does not satisfy the criteria set out in Article 3(1), the
Agency shall forthwith inform the sponsor. Within 90 days of
the sponsor may submit detailed
receipt of
grounds for appeal, which the Agency shall refer to the
Committee. The Committee shall consider whether its opinion
should be revised at the following meeting.

the opinion,

8.
The Agency shall forthwith forward the final opinion of
the Committee to the Commission, which shall adopt a
decision within 30 days of receipt of the opinion. Where, in
exceptional circumstances, the draft decision is not in accord-
ance with the opinion of the Committee, the decision shall be
adopted in accordance with the procedure laid down in Article
73 of Regulation (EEC) No 2309/93. The decision shall be
notified to the sponsor and communicated to the Agency and
to the competent authorities of the Member States.

The designated medicinal product shall be entered in the

9.
Community Register of Orphan Medicinal Products.

Each year the sponsor shall submit to the Agency a
10.
report on the state of development of the designated medicinal
product.

11.
To have the designation of an orphan medicinal product
transferred to another sponsor, the holder of the designation
shall make specific application to the Agency. In consultation
with the Member States, the Agency and interested parties, the
Commission shall draw up detailed guidelines on the form in
which applications for transfer shall be made and the content
of such applications and all the particulars of the new sponsor.

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A designated orphan medicinal product

shall be
12.
removed from the Community Register of Orphan Medicinal
Products:

prejudice to the possibility of applying for a separate marketing
authorisation for other indications outside the scope of this
Regulation.

(a) at the request of the sponsor;

(b) if

it

is established before the market authorisation is
granted that the criteria laid down in Article 3 are no
longer met in respect of the medicinal product concerned;

(c) at the end of the period of market exclusivity as laid down

in Article 8.

Article 6

Protocol assistance

1.
The sponsor of an orphan medicinal product may, prior
to the submission of an application for marketing author-
isation. request advice from the Agency on the conduct of the
various tests and trials necessary to demonstrate the quality,
safety and efficacy of the medicinal product,
in accordance
with Article 51(j) of Regulation (EEC) No 2309/93.

2.
The Agency shall draw up a procedure on the develop-
ment of orphan medicinal products, covering regulatory assis-
tance for the definition of the content of the application for
authorisation within the meaning of Article 6 of Regulation
(EEC) No 2309/93.

Article 7

Community marketing authorisation

1.
The person responsible for placing on the market an
orphan medicinal product may request that authorisation to
place the medicinal product on the market be granted by the
Community in accordance with the provisions of Regulation
(EEC) No 2309/93 without having to justify that the medicinal
product qualifies under Part B of the Annex to that Regulation.

A special contribution from the Community, distinct
2.
from that provided for in Article 57 of Regulation (EEC) No
2309/93, shall be allocated every year to the Agency. The
contribution shall be used exclusively by the Agency to waive,
in part or in total, all the fees payable under Community rules
adopted pursuant to Regulation (EEC) No 2309/93. A detailed
report of the use made of this special contribution shall be
presented by the Executive Director of the Agency at the end of
each year. Any surplus occurring in a given year shall be
carried forward and deducted from the special contribution for
the following year.

3.
The marketing authorisation granted for an orphan medi-
cinal product shall cover only those therapeutic indications
which fulfil the criteria set out in Article 3. This is without

Article 8

Market exclusivity

1. Where a marketing authorisation in respect of an orphan
medicinal product is granted pursuant to Regulation (EEC) No
2309/93 or where all
the Member States have granted
marketing authorisations in accordance with the procedures for
mutual recognition laid down in Articles 7 and 7a of Directive
65/65/EEC or Article 9(4) of Council Directive 75/319/EEC of
20 May 1975 on the approximation of provisions laid down
by law, regulation or administrative action relating to medicinal
products (1), and without prejudice to intellectual property law
or any other provision of Community law, the Community and
the Member States shall not, for a period of 10 years, accept
another application for a marketing authorisation, or grant a
marketing authorisation or accept an application to extend an
existing marketing authorisation, for the same therapeutic indi-
cation,

in respect of a similar medicinal product.

2.
This period may however be reduced to six years if, at the
end of the fifth year, it is established, in respect of the medi-
cinal product concerned, that the criteria laid down in Article 3
are no longer met, inter alia, where it is shown on the basis of
available evidence that the product is sufficiently profitable not
to justify maintenance of market exclusivity. To that end, a
Member State shall inform the Agency that the criterion on the
basis of which market exclusivity was granted may not be met
and the Agency shall then initiate the procedure laid down in
Article 5. The sponsor shall provide the Agency with the
information necessary for that purpose.

By way of derogation from paragraph 1, and without
3.
prejudice to intellectual property law or any other provision of
Community law, a marketing authorisation may be granted, for
the same therapeutic indication, to a similar medicinal product
if:

(a) the holder of the marketing authorisation for the original
orphan medicinal product has given his consent to the
second applicant, or

(b) the holder of the marketing authorisation for the original
orphan medicinal product is unable to supply sufficient
quantities of the medicinal product, or

(c) the second applicant can establish in the application that
the second medicinal product, although similar to the
orphan medicinal product already authorised, is safer, more
effective or otherwise clinically superior.

The Commission shall adopt definitions of ‘similar medi-
4.
cinal product’ and ‘clinical superiority’ in the form of an imple-
menting Regulation in accordance with the procedure laid
down in Article 72 of Regulation (EEC) No 2309/93.

The Commission shall draw up detailed guidelines for the
5.
application of this Article in consultation with the Member
States, the Agency and interested parties.

(1) OJ L 147, 9.6.1975, p. 13. Directive as last amended by Council

Directive 93/39/EEC (OJ L 214, 24.8.1993, p. 22).

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Article 9
Other incentives
1. Medicinal products designated as orphan medicinal prod-
ucts under the provisions of this Regulation shall be eligible for
incentives made available by the Community and by the
Member States to support research into, and the development
and availability of, orphan medicinal products and in particular
aid for research for small- and medium-sized undertakings
provided for in framework programmes for research and tech-
nological development.
2.
Before 22 July 2000, the Member States shall communi-
cate to the Commission detailed information concerning any
measure they have enacted to support research into, and the
development and availability of, orphan medicinal products or
medicinal products that may be designated as such. That infor-
mation shall be updated regularly.
Before 22 January 2001, the Commission shall publish a
3.
detailed inventory of all
incentives made available by the
Community and the Member States to support research into,

and the development and availability of, orphan medicinal
products. That inventory shall be updated regularly.

Article 10

General report

Before 22 January 2006,
the Commission shall publish a
general report on the experience acquired as a result of the
application of this Regulation, together with an account of the
public health benefits which have been obtained.

Article 11

Entry into force

This Regulation shall enter into force on the day of its publica-
tion in the Official Journal of the European Communities.

It shall apply as from the date of adoption of the implementing
Regulations provided for in Article 3(2) and Article 8(4).

This Regulation shall be binding in its entirety and directly applicable in all Member States.

Done at Brussels, 16 December 1999.

For the European Parliament

The President

N. FONTAINE

For the Council

The President

K. HEMILÄ