Amended proposal for a European Parliament and Council Regulation (EC) on orphan medicinal products
Date: 1999-06-15
Institutions: European Commission
Subjects: European Medicines Agency, marketing, medical research, medicinal product, public health

27.6.2000

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Official Journal of the European Communities

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II

(Preparatory Acts)

COMMISSION

Amended proposal for a European Parliament and Council Regulation on orphan medicinal
products (1)

(2000/C 177 E/01)

COM(1999) 298 final (cid:151) 98/0240(COD)

(Submitted by the Commission pursuant to Article 250(2) of the EC-Treaty 16 June 1999)

(1) OJ C 276, 4.9.1998, p. 7.

INITIAL PROPOSAL

AMENDED PROPOSAL

THE EUROPEAN PARLIAMENT AND THE COUNCIL
OF THE EUROPEAN UNION,

Unchanged

Having regard to the Treaty establishing the European
Community, and in particular Article 100A thereof,

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

Having regard to the proposal from the Commission,

Unchanged

Having regard to the opinion of
Committee,

the Economic and Social

Acting in accordance with the procedure laid down in Article
189 B of the EC Treaty,

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

Unchanged

(1) Whereas some conditions occur so infrequently that the
cost of developing 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; whereas the pharmaceutical industry would be
unwilling to develop the medicinal product under normal
market conditions; whereas these medicinal products are
therefore called (cid:145)orphan(cid:146);

(2) Whereas patients suffering from rare conditions should be
entitled to the same quality of treatment as other patients;
whereas it is therefore necessary to stimulate the research,
development and bringing to the market of appropriate
industry; whereas
medications by the pharmaceutical
incentives
the development of orphan medicinal
products have been available in the United States since
1983 and in Japan since 1993;

for

(3) Whereas, 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
products; whereas such action is best taken at Community
in order to take advantage of the widest possible
level
market and to avoid the dispersion of limited resources;
whereas action at Community level is preferable to unco-
ordinated measures by the Member States which may
result in distortions of competition and barriers to intra-
Community trade;

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INITIAL PROPOSAL

AMENDED PROPOSAL

(4) Whereas orphan medicinal products eligible for incentives
should be easily and unequivocally identified; whereas it
seems most appropriate to achieve this result through the
establishment of an open and transparent Community
procedure for
the designation of potential medicinal
products as orphan medicinal products;

the

(5) Whereas objective criteria for designation should be estab-
lished; whereas these criteria should be based on the
prevalence of
condition for which diagnosis,
prevention or treatment is sought; whereas a prevalence
of no more than five affected persons per ten thousand is
generally regarded as the appropriate threshold; whereas
life-threatening,
medicinal products
debilitating
or
seriously
communicable condition should be eligible even when
the prevalence is higher than five per ten thousand;

for
a
seriously

debilitating

intended

the

(5) Whereas objective criteria for designation should be estab-
lished; whereas these criteria should be based on the
prevalence of
condition for which diagnosis,
prevention or treatment is sought; whereas a prevalence
of no more than five affected persons per ten thousand is
generally regarded as the appropriate threshold; whereas
medicinal products
life-threatening,
seriously debilitating or serious and chronic condition
should be eligible even when the prevalence is higher
than five per ten thousand;

intended

for

a

Unchanged

associations,

for designation; whereas

(6) Whereas a Committee composed of experts appointed by
the Member States should be established to examine
this Committee
applications
representatives of
should in addition include
the
patients’
Commission, and three other persons, also designated
by the Commission, on a recommendation from the
Agency; whereas the Agency should be responsible for
the adequate coordination between the Committee on
and the Committee on
orphan medicinal products
proprietary medicinal products;

three
be

designated

by

to

(7) Whereas patients with such conditions deserve the same
quality, safety and efficacy in medicinal products as other
patients; whereas orphan medicinal products
should
therefore be submitted to the normal evaluation process;
whereas sponsors of orphan medicinal products should
have the possibility of obtaining a Community author-
isation; whereas, in order to facilitate the granting of a
Community authorisation, fee to be paid to the Agency
should be waived at least in part; whereas the Community
budget should compensate the Agency for the loss in
revenue thus occurred;

(7) Whereas patients with such conditions deserve the same
quality, safety and efficacy in medicinal products as other
patients; whereas orphan medicinal products
should
therefore be submitted to the normal evaluation process;
whereas sponsors of orphan medicinal products should
have the possibility of obtaining a Community author-
isation; whereas,
in order to facilitate the granting or
the maintenance of a Community authorisation, fees to
be paid to the Agency should be waived at least in part;
whereas the Community budget should compensate the
Agency for the loss in revenue thus occurred;

(8) Whereas experience in the United States and Japan shows
that the strongest incentive for industry to invest in the
development and marketing of orphan medicinal products
is the prospect of obtaining market exclusivity for a
certain number of years during which part of
the
investment might be recovered; whereas data protection
under Article 4(8)(a)(iii) of Council Directive 65/65 is not
sufficient
that purpose; whereas market
exclusivity should however be limited to the therapeutic
indication for which orphan medicinal product desig-
nation has been obtained; whereas,
in the interest of
patients,
the market exclusivity granted to an orphan
medicinal product should not prevent the marketing of
a similar medicinal which is safer, more effective or
otherwise clinically superior;

incentive for

(8) Whereas experience in the United States and Japan shows
that the strongest incentive for industry to invest in the
development and marketing of orphan medicinal products
is the prospect of obtaining market exclusivity for a
certain number of years during which part of
the
investment might be recovered; whereas data protection
under Article 4(8)(a)(iii) of Council Directive 65/65 is not
incentive for that purpose; whereas Member
sufficient
States
this
measure without a Community dimension as such a
provision would be contradictory to Directive 65/65/EEC;
whereas if such measures were adopted in an uncoor-
dinated manner by the Member States, this would create
obstacles to intra-Community trade, leading to distortions
of competition and running contrary to a single market;

independently

introduce

cannot

acting

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INITIAL PROPOSAL

AMENDED PROPOSAL

has

designation
to

whereas market exclusivity should however be limited to
the therapeutic indication for which orphan medicinal
obtained, without
product
prejudice
rights;
whereas, in the interest of patients, the market exclusivity
granted to an orphan medicinal product should not
the marketing of a similar medicinal which
prevent
could be of significant benefit to those affected by the
condition;

been
intellectual

property

existing

Unchanged

(9) Whereas

of

sponsors

orphan medicinal

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

these grants

(10) Whereas the specific programme Biomed 2, of the Fourth
Framework Programme for research and technological
support
development
research on the
(1994-1998),
treatment of rare diseases,
including methodologies for
rapid schemes for the development of orphan medicinal
products and inventories of available orphan medicinal in
to promote the estab-
Europe; whereas
lishment of cross national cooperation in order
to
implement basic and clinical research on rare diseases;
research on rare diseases continue to be a
whereas
priority for
the Commission, as it has been in the
Commission’s Fifth Framework Programme (1998-2002)
for
research and technological development; whereas
this Regulation establishes a legal framework which will
the
allow the swift and effective implementation of
outcome of this research;

(10) Whereas the specific programme Biomed 2, of the Fourth
Framework Programme for research and technological
supported research on the
development
(1994-1998),
treatment of rare diseases,
including methodologies for
rapid schemes for the development of orphan medicinal
products and inventories of available orphan medicinal in
Europe; whereas these grants were to promote the estab-
lishment of cross national cooperation in order
to
implement basic and clinical research on rare diseases;
whereas research on rare diseases continues to be a
priority for the Community, as it has been included in
the
Programme
(1998-2002) for research and technological development;
whereas this Regulation establishes a legal
framework
which will allow the swift and effective implementation
of the outcome of this research;

Commission’s

Framework

Fifth

Unchanged

in

its

the Commission,

(11) Whereas rare diseases have been identified as a priority
area for Community action within the framework for
action in the field of public health (COM(93) 559 final);
whereas
communication
concerning a programme of Community action on rare
diseases within the framework for action in the field of
public health (COM(97) 225 final) has decided to give rare
diseases priority within the public health framework;
whereas
the Commission has proposed a European
Parliament and Council Decision adopting a programme
of Community action 1999-2003 on rare diseases in the
context of the framework for action in the field of public,
including actions to provide information, to deal with
clusters of rare diseases in a population and to support
relevant patient organisations; whereas this Regulation
carries out one of
laid down in this
the priorities
programme of action.

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INITIAL PROPOSAL

AMENDED PROPOSAL

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 bringing to the market of designated orphan
medicinal products.

Article 2

Scope and definitions

For the purpose of this Regulation:

(cid:151) medicinal product means a medicinal product for human use,

as defined in Article 2 of Directive 65/65/EEC,

(cid:151) orphan medicinal

a medicinal product
designated under the terms and conditions of this Regu-
lation,

product means

(cid:151) sponsor means any legal or natural person, established in
the Community, seeking to obtain the designation of a
medicinal product as orphan medicinal product,

(cid:151) sponsor means any legal or natural person, established in
the Community, seeking to obtain or who has obtained the
designation of a medicinal product as orphan medicinal
product,

(cid:151) Agency means the European Agency for the Evaluation of

Unchanged

Medicinal Products.

Article 3

Criteria for designation

if

A medicinal product
its

shall be designated as orphan
1.
medicinal product
the
sponsor can establish that
medicinal product is intended for the diagnosis, prevention
or treatment of a condition affecting less than five per ten
thousand persons in the Community at
the
application is made and that
there exists no satisfactory
method of diagnosis, prevention or treatment of the considered
if
condition that has been authorised in the Community or,
such method exists, that it can reasonably be expected that the
medicinal product will be safer, more effective or otherwise
clinically superior.

the time that

2.
Notwithstanding paragraph 1, a medicinal product may
also be designated as orphan medicinal product if its sponsor
can establish that the medicinal product is intended for a life-
threatening, or seriously debilitating communicable condition
is unlikely that, without
in the Community and that
incentives,
in the
Community would generate sufficient return to justify the
necessary investment.

the medicinal product

the marketing of

it

if

A medicinal product
its

shall be designated as orphan
1.
medicinal product
the
sponsor can establish that
medicinal product is intended for the diagnosis, prevention
or treatment of a condition affecting less than five per ten
thousand persons in the Community at
the
application is made and that
there exists no satisfactory
method of diagnosis, prevention or treatment of the considered
if
condition that has been authorised in the Community or,
such method exists,
the medicinal product will be of
significant benefit to those affected by the condition.

the time that

that

2.
Notwithstanding paragraph 1, a medicinal product may
also be designated as orphan medicinal product if its sponsor
can establish that the medicinal product is intended for the
life-threatening,
diagnosis, prevention or
seriously debilitating or a serious and chronic condition in
the Community and that it is unlikely that, without incentives,
the marketing of the medicinal product in the Community
would generate sufficient
return to justify the necessary
investment.

treatment of

a

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INITIAL PROPOSAL

AMENDED PROPOSAL

3.
The Commission shall, in consultation with the Member
States, the Agency, and interested parties, draw up detailed
guidance for the application of this Article.

Unchanged

Article 4

Committee for Orphan Medicinal Products

A Committee for Orphan Medicinal Products, hereinafter

1.
referred to as (cid:145)the Committee(cid:146), is hereby set up.

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

1.
referred to as (cid:145)the Committee(cid:146),
European Agency for the Evaluation of Medicinal Products.

2.

The task of the Committee shall be:

Unchanged

(a) to examine any application for designation of a medicinal
product as orphan medicinal product which is submitted to
it in accordance with this Regulation,

(b) upon request,
lishment
product policy for the European Union,

to advise the Commission on the estab-
an orphan medicinal

and development of

(c) to assist the Commission in international liaison on matters
relating to orphan medicinal products, particularly the
United States and Japan, and in liaisons with patients
support groups.

The Committee shall consist of one member nominated
3.
by each Member State,
three members nominated by the
Commission to represent patient 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 shall be chosen by reason of
their role and experience in treatment of or research into rare
diseases.

The Committee shall consist of one member nominated
3.
by each Member State,
three members nominated by the
Commission to represent patient organisations and three
members nominated by the Commission on the basis of a
the
recommendation from the Agency. The members of
Committee shall be appointed for a term of
three years
which shall be renewable. Where necessary they may seek
the assistance of an expert.

The Committee shall elect its Chairman for a term of

4.
three years, renewable once.

Unchanged

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 information of the kind
covered by the obligation of professional secrecy.

Article 5

Procedure for designation

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

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

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INITIAL PROPOSAL

AMENDED PROPOSAL

The application shall be accompanied by the following

2.
particulars and documents:

Unchanged

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

sponsor,

(b) the name of the active ingredient(s)

(c) proposed therapeutic indication,

Unchanged

(d) the justification that Article 3 paragraph 1 or 2 is

applicable.

The Commission shall, in consultation with the Member
the Agency and interested parties, draw up detailed
in which applications

3.
States,
guidance on the format and content
for designation are to be presented.

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

it may request

sponsor

5.
The Agency shall ensure that an opinion is given by the
Committee within 60 days of the receipt of a valid 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 consist of the position
of the majority of members. The opinion may be obtained by
written procedure.

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

the members of

two-thirds of

the Committee is

7. Where the opinion of
the
application does not satisfy the criteria set out in Article 3
paragraph 1, the Agency shall forthwith inform the sponsor.
Within 30 days of receipt of the opinion, the sponsor may
submit detailed grounds for appeal, which the Agency shall
refer
consider
whether its opinion should be revised at the following meeting.

to the Committee. The Committee

shall

that

Unchanged

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,
exceptionally, 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 72 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.

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INITIAL PROPOSAL

AMENDED PROPOSAL

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

11.
In order to secure the transfer to another sponsor of the
designation of an orphan medicinal product, the holder of that
designation shall submit a specific application to the Agency. In
consultation with the Member States,
the Agency and the
interested parties,
the Commission shall draw up detailed
guidance concerning the form in which transfer applications
must be submitted and also the contents of such applications.

Article 6

Protocol assistance

Unchanged

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.

The Agency shall draw up a procedure on the devel-
2.
opment of orphan medicinal products, which shall cover in
particular:

(a) assistance in the development of a protocol and for the

follow up of clinical investigations;

(a) assistance in the development of a protocol for pre-clinical
and clinical trials during the development phase and for the
follow up of clinical investigations;

(b) regulatory assistance for the definition of the content of the
application for authorisation within the meaning of Article
6 of Council Regulation (EEC) No 2309/93.

Unchanged

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 any part of the Annex to that Regu-
lation.

2.
A special contribution from the Community, distinct
from that provided for in Article 57 of Regulation (EEC) No
2309/93, will be allocated every year to the Agency. This
contribution will be used exclusively by the Agency to waive,
in part or in total, 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.

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INITIAL PROPOSAL

AMENDED PROPOSAL

3.
The marketing authorisation granted for an orphan
medicinal product shall cover only those therapeutic indi-
cations which fulfil the criteria set out in Article 3. This is
without prejudice to the possibility to apply for a separate
marketing authorisation for other
indications outside the
scope of this Regulation.

Article 8

Market exclusivity

1. Where a marketing authorisation is granted pursuant to
Regulation (EEC) No 2309/93 in respect of an orphan
the Community and the Member States
medicinal product
shall not, for a period of ten years, accept another application
for a marketing authorisation, nor grant a marketing author-
isation or extend an existing marketing authorisation, for the
same therapeutic indication, in respect of a similar medicinal
product.

1. Where a marketing authorisation is granted pursuant to
Regulation (EEC) No 2309/93 or when all Member States have
granted marketing authorisations according to the procedures
for mutual
recognition foreseen in Articles 7 and 7a of
Directive 65/65/EEC or Article 9(4) of Directive 75/319/EEC
in respect of an orphan medicinal product and without
law on intellectual
prejudice
property or any other provision of Community law,
the
Community and the Member States shall not, for a period of
ten years, accept another application for a marketing author-
isation, nor grant a marketing authorisation or extend an
existing marketing authorisation, for the same therapeutic indi-
cation, in respect of a similar medicinal product.

to the provisions of

the

This period may however be reduced to six years if, at
2.
the end of the fifth year, a Member State can establish that the
criteria laid down in Article 3 are no longer met in respect of
the medicinal product concerned or that the price charged for
the medicinal product concerned is such that it allows the
earning of an unreasonable profit. To this end, the Member
State shall initiate the procedure laid down in Article 5.

Unchanged

By derogation to paragraph 1, and without prejudice to
3.
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 of the original
orphan medicinal product has given his consent to the
second applicant, or

(b) the holder of the marketing authorisation of 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
to the
safer,

the second medicinal product, although similar
orphan medicinal product already authorised,
more effective or otherwise clinically superior.

is

At

4.
the end of
orphan medicinal product
Community Register of Orphan Medicinal Products.

the period of market exclusivity,

the
removed from the

shall be

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INITIAL PROPOSAL

AMENDED PROPOSAL

For the purpose of

5.
product(cid:146) means one which consists of:

this Article, a (cid:145)similar medicinal

including isomers and mixture of

(cid:151) the same chemical active substance or active moiety of the
isomers,
substance,
derivatives,
complexes,
provided that
and toxicological
activities of the latter are qualitatively and quantitatively
identical to those of the original product,

the pharmacological

non-covalent

esters,

other

(cid:151) a substance with the same biological activity (including
those that differ from the original substance in molecular
structure, source material and/or manufacturing process)
said
provided that
the pharmacological
to
substance is qualitatively and quantitatively identical
that of the original product,

activity of

(cid:151) a substance with the same radiopharmaceutical activity
(including those with a different radionuclide, ligand, site
of labelling or molecule-radionuclide coupling mechanism)
provided that its diagnostic or therapeutic indications are
identical to those of the original product.

The Commission shall, in consultation with the Member
the Agency and interested parties, draw up detailed

6.
States,
guidance for the application of this Article.

Article 9

Other incentives

The Commission shall adopt definitions of

5.
(cid:145)similar
medicinal product(cid:146) and of (cid:145)clinical superiority(cid:146) in the form of
an implementing Regulation, in accordance with the procedure
laid down in Article 72 of Regulation (EEC) No 2309/93, at the
latest one year after the adoption of the present regulation.

The Commission shall, in consultation with the Member
the Agency and interested parties, draw up detailed
including the

6.
States,
guidance for the application of
implementing Regulation.

this Article,

1. Medicinal products designated as orphan medicinal
products under the provisions of
this Regulation shall be
eligible for incentives made available by the Community and
by the Member States to support the research, development
and availability of orphan medicinal.

1. Medicinal products designated as orphan medicinal
products under the provisions of
this Regulation shall be
eligible for incentives made available by the Community and
by the Member States to support the research, development
and availability of orphan medicinal products and in particular
aid for research for Small and Medium Enterprises provided
under the Fifth Framework Programme for Research and Tech-
nological Development.

2. Within six months of the adoption of this Regulation, the
Member States shall communicate to the Commission detailed
information about the measures they have enacted to support
the research, development and availability of orphan medicinal
products. This information shall be updated on a regular basis.

2. Within six months of the adoption of this Regulation, the
Member States shall communicate to the Commission detailed
information about any measures they may have enacted to
support the research, development and availability of orphan
medicinal products. This information shall be updated on a
regular basis.

3. Member States shall also consider waiving, in part or in
total, the fees to be paid in respect of applications to place
orphan medicinal products on the market.

Deleted

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INITIAL PROPOSAL

AMENDED PROPOSAL

4. Within one year from the adoption of this Regulation,
the Commission shall publish a detailed inventory of all
available by the Community and the
incentives made
Member States to support the research, development and avail-
ability of orphan medicinal products. This inventory will be
updated on a regular basis.

3. Within one year from the adoption of this Regulation,
the Commission shall publish a detailed inventory of all
available by the Community and the
incentives made
Member States to support the research, development and avail-
ability of orphan medicinal products. This inventory will be
updated on a regular basis.

Article 10

General report

Unchanged

Within six years of the entry into force of this Regulation, the
Commission shall publish a general report on the experience
acquired as a result of the application of this Regulation.

Article 11

Entry into force

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

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