Communication from the Commission on Regulation (EC) No 141/2000 of the European Parliament and of the Council on orphan medicinal products
Date: 2003-07-29
Institutions: European Commission
Subjects: drugs classification, market approval, medicinal product, pharmaceutical legislation

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Communication from the Commission on Regulation (EC) No 141/2000 of

the European

Parliament and of the Council on orphan medicinal products

(2003/C 178/02)

Regulation (EC) No 141/2000 (1) of the European Parliament
and of the Council of 16 December 1999 on orphan medicinal
products entered into force on 28 April 2000. It lays down a
Community procedure
the designation of medicinal
products as orphan medicinal products and provides incentives
for the research, development and placing on the market of
designated orphan medicinal products.

for

the Regulation,

the
In accordance with article 3(2) of
Commission adopted Commission Regulation
(EC) No
847/2000 (2), of 27 April 2000 laying down the provisions
for
the criteria for designation of a
medicinal product as an orphan medicinal product and defi-
nitions of the concepts ‘similar medicinal product’ and ‘clinical
superiority’.

implementation of

Following the first three successful years of application of the
Regulation and in response to a number of requests for inter-
pretation and clarification, the Commission wishes to set out
its position on certain matters relating to the implementation
of the designation and market exclusivity provisions. These
interpretations are intended to provide guidance
to the
the Member States,
European Medicines Evaluation Agency,
the pharmaceutical
interested parties.
industry and other
Also, several clarifications are provided in order to avoid a
departure from the spirit of the Regulation.

This Communication, therefore, considers points in relation to
Articles 3 (criteria for designation), 5 (procedure for desig-
nation and removal
from the register), and 7 (Community
marketing authorisation) of the Regulation.

In addition, the Commission is obliged to draw up detailed
guidelines on the application of Article 8 of Regulation (EC)
No 141/2000. This obligation is met in part by section D on
market exclusivity (Article 8) in this Communication.

This Communication should be read in the context of the
current interpretative texts and guidance documents for the
Regulation listed in Annex 1.

A. CRITERIA FOR DESIGNATION — ARTICLE 3.1

1. Products intended for the diagnosis or prevention of a

condition

Article 3(1) of the Regulation states that ‘A medicinal product
its
shall be designated as an orphan medicinal product
sponsor can establish:

if

(1) OJ L 18, 22.1.2000, p. 1.
(2) OJ L 103, 28.4.2000, p. 5.

(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,
is intended for the diagnosis, prevention or
or that
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 return to justify the necessary investment; and

it

(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.’

With regard to the criteria envisaged for designation of an
orphan medicinal product the terms of the Regulation do not
distinguish between the concepts of a medicinal product
intended for the treatment of a condition and a medicinal
product
the diagnosis or prevention of a
condition (e.g. vaccines). One of the criteria to be met relates
to either the number of people affected by the condition or to
the fact
the return on the marketing of a medicinal
product would not be expected to justify the investment in
its development.

intended for

that

In the case of a medicinal product intended for the diagnosis or
prevention of a condition,
the
condition may be interpreted in several ways.

the population ‘affected by’

this may result

If a product for the diagnosis or prevention of a condition is
effective,
in a decrease in the population
actually suffering from the disease or condition to less than
five in 10 thousand persons in the European Community. The
objective of the Regulation is to provide incentives for the
such
development of orphan medicinal products where
incentives are needed. Therefore,
in the case of medicinal
products intended for diagnosis or prevention, the Commission
considers that
those persons
the prevalence calculation of
affected by the condition shall be based on the population to
which such a product is expected to be administered on an
annual basis.

following successful vaccination campaigns,
For example,
although the
the
vaccinated population is
prevalence of the condition in question may be very low.
The prevalence calculation in these cases shall be based on
the population vaccinated on an annual basis.

large,

very

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2. Prevalence of a condition outside the Community

Article 3(1)(a) of the Regulation concerns the prevalence of a
condition. It requires conditions which may be considered as
orphan to affect ‘not more than five in 10 thousand persons in
the Community’. Since prevalence as described in the Regu-
lation refers only to the number of persons affected within
the Community, the prevalence of the disease or condition
outside the Community has no influence on the interpretation
intended to treat a
of
condition which affects a large number of people in certain
countries but which has a low prevalence in the European
Community, is therefore eligible for designation as an orphan
medicinal product with respect to the prevalence criterion, and
if all other criteria are met, eligible for the benefits set out in
the Regulation.

these criteria. A medicinal product

3. Satisfactory method authorised in the Community

the

treatment of

The first alternative in Article 3(1)(b) states that the sponsor
has to establish ‘that there exists no satisfactory method of
condition in
diagnosis, prevention or
question that has been authorised in the Community’.
In
order to ensure consistency of application and to aid applicants
considered
in providing
In
important
this context, Commission Regulation (EC) 847/2000 asks the
applicant to provide details of the ‘existing methods, which
may include authorised medicinal products, medical devices
or other methods of diagnosis, prevention or
treatment
which are used in the Community.’

is
‘satisfactory’ method.

to clarify the notion of

justification,

appropriate

it

safety, quality and efficacy as

A treatment
for a particular disease or condition may be
associated with certain risks. These risks are balanced against
the expected benefits when considering whether to grant or
refuse a marketing authorisation in accordance with the
laid down in
criteria of
Directive 2001/83/EC (1). A marketing
authorisation is
granted if the risk/benefit assessment is positive. Therefore, at
the grant of a marketing authorisation in
the time of
accordance with EU legislation,
the authorised medicinal
product is considered to be a satisfactory method as referred
to in Article 3(1)(b). This being the case, applicants for orphan
designation should seek to show an assumption of significant
benefit over any existing authorised medicinal product
in
accordance with the second part of paragraph Article 3(1)(b),
rather
than seeking to show that an existing authorised
medicinal product is not a satisfactory method.

to the terms of
the off-label use of

Any reference to an already authorised medicinal product can
the marketing authorisation.
only refer
an authorised medicinal
Therefore
product
in accordance with the approved
Summary of Product Characteristics of the product cannot be
considered as a satisfactory method for the purposes of Article
3(1)(b).

(i.e. use not

Commonly used methods of diagnosis, prevention or treatment
that are not subject to marketing authorisation (e.g. surgery,
medical devices) may be considered satisfactory methods if
there is scientific evidence as to the value of such method(s).
The assessment as to whether a particular method may be
considered satisfactory shall take into account the experience
with the method in question, documented results, and other
factors including whether or not the method is invasive and/or
requires hospitalisation.

4. Significant benefit

Article 3(1)b further states that in the case where a satisfactory
method of diagnosis, prevention or treatment of the condition
exists, the sponsor has to establish ‘that the medicinal product
will be of
to those affected by that
condition’.

significant benefit

Significant benefit is defined in Commission Regulation (EC)
‘a clinically relevant advantage or a major
847/2000 as
contribution to patient care.’ The applicant
is required to
establish significant benefit compared with an existing auth-
orised medicinal product or method at the time of designation.
As there may be little or no clinical experience with the orphan
medicinal product in question, the justification for significant
benefit is likely to be made on assumptions of benefit by the
applicant.
In all cases the Committee on Orphan Medicinal
Products (COMP) is required to assess whether or not these
data/evidence
assumptions
supplied by the applicant.

supported

available

are

by

by

the

through

applicant

In all cases the assumption of significant benefit must be
justified
of
evidence/data, which must be considered in the light of the
particular characteristics of
the condition and the existing
methods. Thus different considerations such as ease of self-
administration may be considered a benefit if the patient is
ambulant, but may not be considered a benefit if the patient
is likely to be hospitalised during treatment.

provision

the

the Community is generally deemed to fulfil

In this context, a medicinal product authorised in one Member
State of
the
criteria of ‘authorised in the Community’. It is not necessary
for the product to have either a Community authorisation or
for it
to be
to be authorised in all Member States for it
considered as ‘authorised in the Community’.

(1) OJ L 311, 28.11.2001, p. 67.

If the argument for significant benefit is based on an increase
in supply/availability of the method, the sponsor must provide
details of the supply/availability problem and explain why this
results in the unmet needs of patients. All claims should be
substantiated by qualitative and quantitative references. If the
supply of existing methods is sufficient to meet patients' needs
in the orphan indication an increase in supply will not be
viewed as a significant benefit.

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With respect to potential availability of the product to the
Community population, a medicinal product that is authorised
and available in all Member States may constitute a significant
benefit compared with a similar product that is authorised in a
limited number of Member States only.

Supply problems, which arise from manufacturing process
limitations should be differentiated from those which arise
‘artificially’, e.g. due to cost limitations or health care policy.
Where supply/availability problems with existing methods are
of a transient nature, e.g. due to manufacturing problems, it
will not be possible generally for sponsors to argue significant
benefit based on supply problems unless it can be shown to be
a recurring problem or a long term interruption in supply.

— due to limited source of starting materials (e.g. plasma-

derived medicinal products),

— limitation in scale of manufacturing process

(e.g.

fermentation),

— long term interruption in supply of authorised product (e.g.

due to manufacturing difficulties).

a product

in compliance with the

It should be noted that the enhancement of the pharmaceutical
quality of
relevant
Committee on Proprietary Medicinal Products guidelines is a
part of the obligation of every marketing authorisation holder
and does not constitute a basis
the assumption of
significant benefit
context of orphan medicinal
product designation.

in the

for

In order to provide further examples for guidance, assumptions
of significant benefit may be based on:

— expected benefits
including benefits
method,

to a particular population sub-set,
to the existing
in patients

resistant

— a new source of an existing medicinal product which has
hitherto been sourced from human blood or plasma at risk
of viral or TSE transmission. The risks must be more than
theoretical, e.g.
if there have been documented cases of
viral transmission with a plasma derived product. In any
case, the inherent risks of such a new source material (e.g.
recombinant,
in
perspective for the assumption of significant benefit,

transgenic) would also have to be put

— expectations of a clinically relevant improved safety profile.
The reasons for these expectations must be justified, either
by clinical experience or exceptionally by reference to the
pharmacological properties of the product,

— justification as to why more favourable and clinically
relevant pharmacokinetic properties compared with the
existing authorised medicinal product can be assumed,

— where there are serious and documented difficulties with
the formulation or route of administration of an authorised
medicinal product, a more convenient formulation or route
may be considered as a significant benefit,

— limitation in availability of authorised product due to

extreme storage conditions,

— insufficient quantity of authorised product on the market

Finally, in view of the Community nature of the orphan desig-
nation process and the fact that by virtue of Article 8(1) the
market exclusivity benefits are linked to a marketing author-
isation in the entire Community, the Commission is concerned
that the process should not be undermined. For example, a
company obtains the designation of a medicinal product as
an orphan medicinal product. It is the right of any sponsor
to decide whether or not to apply for orphan designation and
in cases
to decide on the route for marketing authorisation,
where application via the centralised procedure is not obli-
gatory. However, different mechanisms could be used by
another,
to block
unduly the market exclusivity from which the first company's
product might benefit. For example, the second company could
apply for a marketing authorisation for the same medicinal
product in one Member State without prior application for
designation as an orphan medicinal product. This second
company could then attempt to block the authorisation of
the designated orphan medicinal product on the grounds
either of the presence of a satisfactory method or of failure
to establish significant benefit over this same medicinal product
now authorised in a single Member State.

second company in order

to attempt

The Commission considers that the imminent expectation of a
Community authorisation as compared with the existence of a
national authorisation in one or a limited number of Member
States may be sufficient
to maintain an assumption of
In this situation the designated orphan
significant benefit.
medicinal product will be maintained in the
register,
provided that the criteria are still met.

B. PROCEDURE FOR DESIGNATION AND REMOVAL FROM

THE REGISTER — ARTICLE 5

Article 5 defines the procedure for designation and removal
from the register.

1. Definition of condition in the context of designation of
an orphan medicinal product by the Committee on
Orphan Medicinal Products

The Commission guideline ENT 6283/00 (See Annex 1) defines
a condition as ‘any deviation(s) from the normal structure or
function of the body, as manifested by a characteristic set of
signs and symptoms (typically a recognised distinct disease or a
syndrome)’.

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When considering an application for orphan designation, the
Committee on Orphan Medicinal Products may take into
account
the available data to modify the condition under
application (for example, because the Committee considers
that the designatable condition is broader than the one under
the Committee on Orphan
application).
Medicinal Products
the
the designation for
condition it considers
suitable, provided the criteria laid
down in Article 3(1) are met.

In such cases,

shall grant

During the development of a product, the sponsor may apply
to the Committee on Orphan Medicinal Products to amend the
designated condition provided that the criteria for designation
continue to be met.

2. Reevaluation of designation and /or removal from the

Register

Article 5(12)(b) of the Regulation provides the possibility of
removing a designated orphan medicinal product from the
it is
Community Register of Orphan Medicinal Products ‘if
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’.

This implies that a removal on this basis must be preceded by a
re-evaluation by the Committee on Orphan Medicinal Products
of the criteria laid down in Article 3. Removal in these circum-
stances might occur if there is evidence that the basis on which
the original designation was granted has changed, in particular
when the designation was based on significant benefit which
included an expectation of better clinical efficacy or better
safety.

2.1. Justification of
applicant

continued fulfilment of

the

criteria by the

When a sponsor submits an application for marketing author-
isation for a designated orphan medicinal product, he/she shall
include the information that the product concerned has been
designated as an orphan medicinal product. In addition the
requested to inform the European Medicines
sponsor
Evaluation Agency (EMEA) and to submit a report on the
criteria that
the product as an
orphan medicinal product and updated information on the
current fulfilment of these criteria.

led to the designation of

is

responsible for giving a scientific opinion on initial designation.
As initial designation leads to the inclusion of a medicinal
in the Community Register of Orphan Medicinal
product
it follows that, unless it is at the request of the
Products,
follow the same
from the register must
sponsor, removal
procedure of scientific opinion followed by a legal decision
by the Commission in accordance with Article 5(8).

The Community Register of Orphan Medicinal Products is kept
by the Commission and published on the Commission's
web-site. A medicinal product shall be removed from the
register in accordance with Article 5(12)(b) in the case of a
from the
opinion
Commission decision
Committee on Orphan Medicinal Products that
the criteria
laid down in Article 3, and on which the original decision was
based are no longer met.

following

an

The procedure set out
in Article 5 should be followed
whenever the criteria are reviewed. Similarly, unless it is at
the request of the sponsor, the same procedure should be
followed should the review result in removal from the register.

2.3. Re-evaluation of orphan designation criteria at

time of

Marketing authorisation — preauthorisation phase

According to article 5(12)(b) a designated orphan medicinal
product shall be removed from the Community Register of
Orphan Medicinal Products ‘if
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’.

it

is

imminent,

The Commission interprets this as meaning that the criteria for
orphan designation shall be reviewed before a marketing auth-
orisation is granted. The Commission considers that the most
appropriate
time to reconsider designation is when the
marketing authorisation of a designated orphan medicinal
product
is at around the time of an
expected positive opinion from the Committee on Proprietary
Medicinal Products (CPMP) or at around the time of granting
the
For national
procedures, the competent authorities of the Member States
shall ensure that appropriate information is forwarded to the
EMEA at the time of submission of a marketing authorisation
application for a designated orphan medicinal product.

first national marketing authorisation.

that

The information will be assessed in parallel to the marketing
authorisation assessment. In case of reasonable doubt as to
whether the criteria for designation continue to be met, the
sponsor may be invited to provide additional justification either
orally or in writing.

2.2. Removal from the register

The responsibility for assessing the criteria for orphan desig-
nation rests solely with the Committee on Orphan Medicinal
Products. The Committee on Orphan Medicinal Products is

2.4. Effect of removal from the Community register on marketing

authorisation procedure

the orphan regulation,

a
According to Article 7(1) of
designated orphan medicinal product is entitled to be granted
a Community authorisation in accordance with the provision
of Council Regulation (EEC) No 2309/93 (1) without having to
justify that the medicinal product qualifies under Part B of the
the medicinal
annex to that Regulation. This requires that
product is designated as an orphan medicinal product at the
time of the initial application.

(1) OJ L 214, 24.8.1993, p. 1.

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if a designated medicinal
The Commission considers that,
product is removed from the register after the procedure for
authorisation in accordance with Regulation (EEC) No 2309/93
has commenced,
it may still be granted a Community
marketing authorisation in accordance with that Regulation.
However, the medicinal product will not be entitled to the
subsequent benefits provided for by the Orphan Regulation
(e.g. market exclusivity and future fee reductions). On the
other hand, none of
to the
removal from the register, such as fee reductions, and which
accrued prior to its removal shall be recovered.

the benefits enjoyed prior

C. COMMUNITY MARKETING AUTHORISATION — ARTICLE

7.3

1. Designated condition v authorised indication

Article 7.3 of the Regulation states that ‘the marketing author-
isation granted for an orphan medicinal product shall cover
only those therapeutic indications which fulfil the criteria set
out in Article 3’.

There have been questions regarding the possibility of having a
therapeutic indication authorised in the framework of
the
from
marketing authorisation procedure, which is different
the condition that has been accepted in the designation
procedure. The Commission considers that if orphan desig-
nation and its continuing benefits are to be maintained both
the therapeutic indication applied for and the therapeutic indi-
cation finally authorised are required to fall within the scope of
the designated orphan condition. In order to ensure this the
sponsor may request a revision of the designation decision,
prior
the
amended designation is not accepted by Committee on
Orphan Medicinal Products or if the applicant does not apply
to amend the designation, the authorised indication will not be
a designated ‘orphan indication’ and the product will not
benefit from market exclusivity as foreseen in Article 8.

to the submission of

the MA application.

If

In cases in which the therapeutic indication approved through
the
the marketing authorisation procedure is a subset of
designated orphan condition,
the marketing authorisation
holder will benefit from market exclusivity for this product,
for this indication. If the same sponsor applies subsequently
for a marketing authorisation for a second subset of
the
the product will not benefit
designated orphan condition,
from any additional period of market exclusivity,
for that
second authorised indication,
i.e. the second authorised indi-
cation will be covered by the market exclusivity granted on
initial authorisation. If, however, a different sponsor applies for
a marketing authorisation for a second subset of the designated
orphan condition, a new 10-year period of market exclusivity
can be obtained for that second product, for that second auth-
orised indication.

If it is considered that the second product (from a different
sponsor) is similar to the one that is already authorised and
that it is intended for the same therapeutic indication, i.e. the

same subset of the designated condition, the application can
not be accepted (Article 8(1)), unless any of the derogations set
out in Article 8(3) apply.

The designation as an orphan medicinal product and the grant
of a marketing authorisation are subject to different criteria and
procedures. Therefore, different decisions may be taken relating
to, for example, the designated condition and the authorised
therapeutic indication. As sponsors often apply for orphan
designation at an early stage in the product development, the
sponsor should provide a rationale for use in the proposed
therapeutic indication. When evaluating an application for
designation,
the Committee on Orphan Medicinal Products
will consider an orphan condition in broad terms in order to
avoid designations related to artificial subsets of a particular
condition.

2. Separate marketing authorisation

Article 7(3) provides for the possibility that a sponsor of an
orphan medicinal product can ‘apply for a separate marketing
authorisation for other indications outside the scope of this
is also possible that a
Regulation’. On the other hand it
marketing authorisation holder of a non-orphan medicinal
product may develop the product
in a designated orphan
condition and obtain orphan designation for this new indi-
cation. In both cases Article 7(3) requires that marketing auth-
orisations for orphan medicinal products are handled separately
from marketing authorisations
for non-orphan medicinal
products in order to provide legal certainty that the benefits
of market exclusivity provided by the Regulation can be
enforced.

D. MARKET EXCLUSIVITY — ARTICLE 8

1. MA applications running in parallel

for the same

orphan indication

1.1. Both products subject to marketing authorisation applications
according to Chapter I of Regulation (EEC) No 2309/93

According to Article 8, a marketing authorisation granted for a
designated orphan medicinal product will benefit from a ten
year period of market
certain
conditions continue to be met.

exclusivity provided that

If two applications for marketing authorisation for the same
orphan condition with respect to similar designated orphan
medicinal products are received by the Agency at different
times,
they will be evaluated according to the relevant
provisions of the pharmaceutical legislation. This implies that
the Committee on Proprietary Medicinal Products (CPMP)
provides, as part of its opinion on the MAA, an opinion on
the similarity of the two products and on whether or not they
are intended for the same indication, for example, where there
is a significant overlap of the target population. Following from

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Article 5(12), prior to the grant of a marketing authorisation
the Committee on Orphan Medicinal Products will have to
review, where appropriate,
In
other words, the Committee on Orphan Medicinal Products
will have to verify whether the criteria for designation are
still met.
the designated orphan
the case,
medicinal product shall be removed from the Community
Register.

the decision for designation.

this is not

If

that

the Regulation,

follows from Article 8(1) of

It
if a
marketing authorisation in respect of an orphan medicinal
to Council Regulation
product has been granted pursuant
(EEC) No 2309/93, neither the Community nor the Member
States shall ‘(. . .) grant a marketing authorisation for the same
therapeutic indication in respect of a similar medicinal product’
unless any of the derogations set out in Article 8(3) apply.
Therefore after a Community marketing authorisation has
been granted for one of the products, the other application
will have to be refused unless the second applicant can
establish in the application that the second product is safer,
more effective or otherwise clinically superior.

1.2. Both products running in national procedures

from market exclusivity until

The same rules apply in the cases where national procedures
are used. According to Article 8.1, an orphan medicinal
product does not benefit
‘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’.

Therefore, if two similar designated orphan medicinal products
are subjects of procedures for mutual recognition running in
parallel, the first product which has been granted marketing
authorisations in all Member States will be the one to enjoy the
benefits of market exclusivity preventing any further marketing
authorisations from being granted for the second product
unless any of the derogations set out in Article 8(3) apply.

1.3. One product subject to a marketing authorisation application
made according to Chapter I of Regulation (EEC) No 2309/93
authorisation
to
and
application in the national procedure

a marketing

product

subject

one

The same general rule applies as in the preceding paragraph.
The application of market exclusivity depends on the timing of
the grant of the Community marketing authorisation on the
one hand and the grant of national marketing authorisations in
all Member States on the other. The first of the two cases to be
fulfilled will prevent any (further) marketing authorisation(s) for
the second, unless any of the derogations set out in Article 8(3)
apply.

1.4. Transparency regarding Marketing Authorisation applications

for designated orphan medicinal products

In order to aid transparency, when a sponsor of a designated
submits an application for a
orphan medicinal product
to a national
marketing authorisation to the EMEA or
competent authority,
it is recommended that the competent
authority publish the name (INN) of the active substance of
the designated orphan medicinal product.

2. New orphan indications granted to an authorised

orphan medicinal product

If a sponsor obtains a marketing authorisation for a designated
orphan medicinal product within a particular designated
orphan condition, the product will benefit from a 10 year
period of market exclusivity for the authorised indication. If
the MAH subsequently varies the marketing authorisation to
include another, separate, designated orphan condition, then a
second 10 year period of market exclusivity starting on the
date of approval of the variation shall apply to the second
orphan indication. The second period of exclusivity shall run
in parallel to the first, while maintaining different start and
finish dates.

3. Different orphan indications granted to similar orphan

medicinal products with different sponsors

two sponsors of

similar designated orphan medicinal
If
times for the authorisation of
products apply at different
different orphan conditions,
is possible that one
then it
sponsor would be granted marketing authorisation for an
orphan medicinal product in one orphan condition and the
other sponsor would be granted marketing authorisation for
a similar orphan medicinal for another orphan condition. In
this case, each product would be granted market exclusivity for
the authorised indication only.

4. Article 8(2) Review of market exclusivity at five years

Article 8(2) provides for a reduction in the period of market
exclusivity to six years if it is established at the end of the fifth
year that the criteria laid down in Article 3 are no longer met.
This includes demonstrating, on available evidence, that the
product is sufficiently profitable not to justify the maintenance
of market exclusivity.

in order

The Commission will put in place the necessary procedures
the prices of orphan
to monitor
and systems
medicinal products and in order to determine whether or not
at the end of five years the product is sufficiently profitable not
to justify maintenance of market exclusivity. An important
element of the systems will be the drawing up of detailed
guidelines for the application of Article 8, as required by
Article 8(5) of the Regulation.

In any event, it is recommended that by the end of the fifth
year of market exclusivitys the competent authorities system-
the criteria on which basis
atically check whether or not
market exclusivity was granted are no longer met.
In such
cases,
inform the Agency in
order to instigate the procedure laid down in Article 5.

the competent authority shall

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It

As a further consideration, it is implicit that the criterion of
non-profitability must have been met at the time of orphan
designation.
follows that an orphan medicinal product
should not benefit from market exclusivity if it enjoys raised
levels from the time of marketing. The criterion of
profit
non-profitability should therefore be assessed whenever there
is a review of the criteria for orphan designation, which may
occur at any time.

In order to facilitate regular monitoring of the non-profitability
criterion, the Marketing Authorisation Holder will be asked to
submit information to the Commission and to the Committee
on Orphan Medicinal Products on the marketing, prices and
reimbursement, distribution costs, annual estimate of number
of patients treated or prescriptions, and all other necessary
economic data related to the authorised orphan medicinal
products in all of the Member States.

5. Article 8(3)c — challenging

the 10-year market

exclusivity

Article 8(3) allows a derogation from the market exclusivity
provision if a second applicant for a marketing authorisation
for a similar medicinal product
(be it designated or not)
intended for the same therapeutic indication, can establish
that the second medicinal product is ‘safer, more effective or
otherwise clinically superior’.

In this situation, once the second applicant with a designated
orphan medicinal product succeeds in obtaining a marketing
authorisation for his/her product, he/she will share the market
exclusivity with the first holder for the remaining duration of
the 10-year period of market exclusivity granted to the first
product, until the review foreseen in Article 8(2) is triggered. If
the second product is not designated, the second applicant will
enjoy the benefits of the full period of data protection, but will
not share market exclusivity.

If a third applicant wishes to obtain a MA for a similar product
designated for the same therapeutic indication, he/she will have
to demonstrate that his product is ‘safer, more effective or
otherwise clinically superior’
than any designated products
already authorised. Again, market exclusivity will be shared
until the review foreseen in Article 8(2) is triggered.

6. Market exclusivity and Enlargement

When a designated orphan medicinal product has been auth-
orised throughout the Community and therefore benefits from
market
exclusivity extends auto-
matically to the acceding country on the day of accession,
encompassing the same rights as in the Community.

this market

exclusivity,

National marketing authorisations granted in the candidate
countries before accession do not conflict with the market
exclusivity.

ANNEX 1

1. ENTR/6283/00 Revision 1

Guideline on the Format and Content of Applications for designation as Orphan Medicinal Products (October 2002) and
Annex

2. COMP/436/01 Final

Points to Consider on the Calculation and Reporting of the Prevalence of a Condition for Orphan Designation (COMP
Adopted March 2002)

3. EMEA/14222/00

Procedures for Orphan Medicinal Product Designation — General Principles Revision 2 (25/10/02)

4. EMEA/4795/00

General Information for Sponsors of Orphan Medicinal Products Revision 1 (25/10/02)

5. COMP/50/01

Appeal Procedure for Orphan Product Designation

6. COMP/189/01 Final
Note for Guidance on the Format and Content of the Annual Report on the State of Development of an Orphan
Medicinal Product, (Adopted by COMP April 2002)

7. EMEA/H/238/02
EMEA Guidance for Companies requesting Protocol Assistance regarding Scientific Issues

All of these documents are available on the EMEA website (www.emea.eu.int). In addition document ENTR/6283/00 is
available on the DG enterprise website (pharmacos.eudra.org/F2/)