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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,

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

tions of competition and barriers to intra-Community
trade;(4)orphan medicinal products eligible for incentives shouldbe easily and unequivocally identified; it seems mostappropriate to achieve this result through the establishment of an open and transparent Community procedure
for the designation of potential medicinal products asorphan medicinal products;(5)

objective criteria for designation should be established;those criteria should be based on the prevalence of thecondition for which diagnosis, prevention or treatment
is sought; a prevalence of not more than five affected
persons per 10 thousand is generally regarded as theappropriate threshold; medicinal products intended for alife-threatening, seriously debilitating or serious andchronic condition should be eligible even when theprevalence is higher than five per 10 thousand;(6)

a Committee composed of experts appointed by theMember States should be established to examine applications for designation; 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 recommendation from the European Agency for the Evaluation of
Medicinal Products (hereinafter referred to as ‘the
Agency’); the Agency should be responsible for theadequate coordination between the Committee onorphan medicinal products and the Committee on
proprietary medicinal products;(7)

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 oforphan medicinal products should have the possibilityof obtaining a Community authorisation; in order tofacilitate the granting or the maintenance of 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;

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)some conditions occur so infrequently that the cost ofdeveloping and bringing to the market a medicinal
product to diagnose, prevent or treat 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 undernormal market conditions; these medicinal products arecalled ‘orphan’;(2)patients suffering from rare conditions should be entitled to the same quality of treatment as other patients; itis therefore necessary to stimulate the research, development and bringing to the market of appropriate medications by the pharmaceutical industry; incentives for thedevelopment of orphan medicinal products have been
available in the United States of America since 1983 andin Japan since 1993;(3)

in the European Union, only limited action has beentaken so far, whether at national or at Community level,
to stimulate the development of orphan medicinal products; such action is best taken at Community level inorder to take advantage of the widest possible market
and to avoid the dispersion of limited resources; action
at Community level is preferable to uncoordinated measures 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).

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experience in the United States of America and Japanshows 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; dataprotection under Article 4(8)(a)(iii) of Council Directive
65/65/EEC of 26 January 1965 on the approximation ofprovisions laid down by law, regulation or administrative action relating to medicinal products (1) is not a
sufficient incentive for that purpose; Member States
acting independently cannot introduce such a measure
without a Community dimension as such a provision
would be contradictory to Directive 65/65/EEC; if suchmeasures were adopted in an uncoordinated manner by
the Member States, this would create obstacles to intraCommunity trade, leading to distortions of competition
and running counter to the single market; market exclusivity should however be limited to the therapeutic indication for which orphan medicinal product designation
has been obtained, without prejudice to existing intellectual property rights; in the interest of patients, themarket 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;

22. 1. 2000

framework; the European Parliament and the Council
have adopted Decision No 1295/1999/EC of 29 April
1999 adopting a programme of Community action onrare diseases within the framework for action in the fieldof public health (1999 to 2003) (2), including actions toprovide information, to deal with clusters of rarediseases in a population and to support relevant patientorganisations; this Regulation implements one of thepriorities laid down in this programme of action,

HAVE ADOPTED THIS REGULATION:

Article 1
PurposeThe 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

(9)

(10)

(11)

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 theMember States to support the research and developmentof medicinal products for the diagnosis, prevention ortreatment of such conditions, including rare diseases;

the specific programme Biomed 2, of the fourth framework programme for research and technological development (1994 to 1998), supported research on thetreatment 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 topromote the establishment of cross national cooperationin order to implement basic and clinical research on rarediseases; research on rare diseases continues to be apriority for the Community, as it has been included in
the fifth framework programme for research and technological development (1998 to 2002); this Regulation
establishes a legal framework which will allow the swift
and effective implementation of the outcome of thisresearch;rare diseases have been identified as a priority area for
Community action within the framework for action in
the field of public health; the Commission, in its
communication
concerninga
programmeofCommunity action on rare diseases within the framework for action in the field of public health has decided
to give rare diseases priority within the public health(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).

Definitions
For the purposes of this Regulation:(a) ‘medicinal product’ means a medicinal product for humanuse, as defined in Article 2 of Directive 65/65/EEC;(b) ‘orphan medicinal product’ means a medicinal productdesignated as such under the terms and conditions of thisRegulation;(c) ‘sponsor’ means any legal or natural person, established in
the Community, seeking to obtain or having obtained thedesignation 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
1.
A medicinal product shall be designated as an orphan
medicinal product if its sponsor can establish:(a) that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10 thousand persons in
the Community when the application is made, orthat it is intended for the diagnosis, prevention or treatment 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 returnto justify the necessary investment;(2) OJ L 155, 22.6.1999, p. 1.

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ENand(b) that there exists no satisfactory method of diagnosis,
prevention or treatment of the condition in question thathas 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
1.
A Committee for Orphan Medicinal Products, hereinafterreferred to as ‘the Committee’, is hereby set up within the
Agency.
2.

The task of the Committee shall be:(a) to examine any application for the designation of a medicinal 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 development of a policy on orphan medicinal products for theEuropean Union;

L 18/3the medicinal product before the application for marketing
authorisation is made.
2.
The application shall be accompanied by the following
particulars and documents:(a) name or corporate name and permanent address of thesponsor;(b) active ingredients of the medicinal product;(c) proposed therapeutic indication;(d) justification that the criteria laid down in Article 3(1) are
met and a description of the stage of development,
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 andprepare a summary report to the Committee. Where appropriate, 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 theCommittee within 90 days of the receipt of a valid application.

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

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 majorityof two-thirds of the members of the Committee. The opinion
may be obtained by written procedure.

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

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

4.
The Committee shall elect its Chairman for a term of
three years, renewable once.

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 accordance 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 andto the competent authorities of the Member States.

(c) to assist the Commission in liaising internationally on
matters relating to orphan medicinal products, and inliaising with patient support groups;

5.
The representatives of the Commission and the Executive
Director of the Agency or his representative may attend all
meetings of the Committee.
6.
The Agency shall provide the secretariat of theCommittee.
7.
Members of the Committee shall be required, even after
their duties have ceased, not to disclose any information of thekind covered by the obligation of professional secrecy.

9.
The designated medicinal product shall be entered in theCommunity Register of Orphan Medicinal Products.

Article 510.
Each year the sponsor shall submit to the Agency areport on the state of development of the designated medicinal
product.

Procedure for designation and removal from the register1.
In order to obtain the designation of a medicinal productas an orphan medicinal product, the sponsor shall submit anapplication 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).

11.
To have the designation of an orphan medicinal producttransferred 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, theCommission shall draw up detailed guidelines on the form inwhich applications for transfer shall be made and the content
of such applications and all the particulars of the new sponsor.

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12.
A designated orphan medicinal product shall be
removed from the Community Register of Orphan Medicinal
Products:(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 nolonger met in respect of the medicinal product concerned;(c) at the end of the period of market exclusivity as laid downin Article 8.

Article 6
Protocol assistance1.
The sponsor of an orphan medicinal product may, prior
to the submission of an application for marketing authorisation. request advice from the Agency on the conduct of thevarious tests and trials necessary to demonstrate the quality,
safety and efficacy of the medicinal product, in accordancewith Article 51(j) of Regulation (EEC) No 2309/93.
2.
The Agency shall draw up a procedure on the development of orphan medicinal products, covering regulatory assistance for the definition of the content of the application forauthorisation 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 anorphan medicinal product may request that authorisation toplace the medicinal product on the market be granted by theCommunity 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.
2.
A special contribution from the Community, distinct
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 bepresented by the Executive Director of the Agency at the end ofeach 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 medicinal product shall cover only those therapeutic indications
which fulfil the criteria set out in Article 3. This is without

22. 1. 2000

prejudice to the possibility of applying for a separate marketing
authorisation for other indications outside the scope of thisRegulation.
Article 8Market 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 formutual 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 andthe Member States shall not, for a period of 10 years, accept
another application for a marketing authorisation, or grant amarketing authorisation or accept an application to extend an
existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product.
2.
This period may however be reduced to six years if, at theend of the fifth year, it is established, in respect of the medicinal product concerned, that the criteria laid down in Article 3
are no longer met, inter alia, where it is shown on the basis ofavailable evidence that the product is sufficiently profitable notto justify maintenance of market exclusivity. To that end, aMember State shall inform the Agency that the criterion on thebasis 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 theinformation necessary for that purpose.
3.
By way of derogation from paragraph 1, and without
prejudice to intellectual property law or any other provision ofCommunity law, a marketing authorisation may be granted, forthe same therapeutic indication, to a similar medicinal productif:(a) the holder of the marketing authorisation for the originalorphan medicinal product has given his consent to thesecond applicant, or(b) the holder of the marketing authorisation for the originalorphan medicinal product is unable to supply sufficientquantities of the medicinal product, or(c) the second applicant can establish in the application thatthe second medicinal product, although similar to theorphan medicinal product already authorised, is safer, more
effective or otherwise clinically superior.
4.
The Commission shall adopt definitions of ‘similar medicinal product’ and ‘clinical superiority’ in the form of an implementing Regulation in accordance with the procedure laid
down in Article 72 of Regulation (EEC) No 2309/93.
5.
The Commission shall draw up detailed guidelines for theapplication 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 products under the provisions of this Regulation shall be eligible forincentives made available by the Community and by theMember 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 technological development.
2.
Before 22 July 2000, the Member States shall communicate to the Commission detailed information concerning any
measure they have enacted to support research into, and thedevelopment and availability of, orphan medicinal products ormedicinal products that may be designated as such. That information shall be updated regularly.
3.
Before 22 January 2001, the Commission shall publish adetailed inventory of all incentives made available by theCommunity and the Member States to support research into,

L 18/5and 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 ageneral report on the experience acquired as a result of theapplication 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 publication 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

For the Council

The President

The President

N. FONTAINE

K. HEMILÄ