Guideline on aspects of the application of Article 8(2) of Regulation (EC) No 141/2000 of the European Parliament and of the Council: Review of the period of market exclusivity of orphan medicinal products
Date: 2008-09-23
Institutions: Council of the European Union, European Parliament
Subjects: application of EU law, drugs classification, exclusive distribution agreement, market approval, medicinal product, pharmaceutical legislation

C 242/8

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Official Journal of the European Union

23.9.2008

Guideline on aspects of the application of Article 8(2) of Regulation (EC) No 141/2000 of the
European Parliament and of the Council: Review of the period of market exclusivity of orphan
medicinal products

(2008/C 242/07)

1. INTRODUCTION

‘A medicinal product shall be designated orphan medicinal
product if its sponsor can establish:

Regulation (EC) No 141/2000 of the European Parliament and
of the Council of 16 December 1999 on orphan medicinal
products (1) 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

In accordance with Article 3(2) and 8(4) of Regulation (EC)
No 141/2000,
the Commission adopted Commission Regu-
lation (EC) No 847/2000 of 27 April 2000, laying down the
provisions for implementation of the criteria for designation of
a medicinal product as an orphan medicinal product and defini-
tions of the concepts ‘similar medicinal product’ and ‘clinical
superiority’ (2).

In July 2003, following the first three years of application of
Regulation (EC) No 141/2000, the Commission published a
Communication (3)
sets out general considerations on
certain matters relating to the application of that Regulation.

that

In accordance with Article 10 of Regulation (EC) No 141/2000,
the Commission services adopted in June 2006 a general report
on the experience acquired as a result of the application of
Regulation (EC) No 141/2000 (4).

This guideline sets out the general principles and procedures by
which the period of market exclusivity of orphan medicinal
products is reviewed and may be reduced to six years. If neces-
sary, this guideline will be updated when further experience is
gained on the application of Article 8(2) of Regulation (EC)
No 141/2000 (5).

2. BACKGROUND AND LEGAL BASIS

Designation as an orphan medicinal product is governed by
Articles 3 and 5 of Regulation (EC) No 141/2000. The designa-
tion criteria are laid down in Article 3(1), which reads:

(1) OJ L 18, 22.1.2000, p. 1.
(2) OJ L 103, 28.4.2000, p. 5.
(3) OJ C 178, 29.7.2003, p. 2.
(4) Commission staff working document of 20 June 2006, on the
experience acquired as a result of the application of Regulation (EC)
No 141/2000 on orphan medicinal products and account of the
public health benefits obtained — Document on the basis of
Article 10 of Regulation (EC) No 141/2000, SEC(2006) 832, avail-
able at:
http://ec.europa.eu/enterprise/pharmaceuticals/orphanmp/doc/
orphan_en_06-2006.pdf

(5) Certain principles for this review and possible reduction of market
exclusivity were already contained in Section D.4 of the above-cited
Commission Communication of 2003. However, following additional
experience
application of Regulation (EC)
the Commission developed its interpretation of
No 141/2000,
Article 8(2) further, as set out in the present guideline. Consequently,
the present guideline supersedes Section D.4 of the 2003 Communica-
tion.

gained with the

(a) that it is intended for the diagnosis, prevention or treat-
ment of a life-threatening or chronically debilitating
condition affecting no more than five in 10 thousand
persons in the Community when the application is
made (so-called “prevalence” criterion), or

that 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
in the Community would
of
generate sufficient return to justify the necessary
investment;

the medicinal product

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.’
(emphasis added).

According to Article 8(1) of Regulation (EC) No 141/2000,
where a marketing authorisation in respect of an orphan
medicinal product is granted in all Member States, the Com-
munity and the Member States shall not, for a period of ten
years (6), accept another application for a marketing authorisa-
tion, or grant a marketing authorisation or accept an application
to extend an existing marketing authorisation, for the same
therapeutic indication, in respect of a similar medicinal product.

Article 8(2) of the same Regulation provides that this period
may be reduced to six years (7) if, at the end of the fifth year, it
is established, in respect of the medicinal product concerned,
that the designation 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.

(6) Regulation (EC) No 1901/2006 of the European Parliament and of the
Council of 12 December 2006 on medicinal products for paediatric
use
and amending Regulation (EEC) No 1768/92, Directive
2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004
(OJ L 378, 27.12.2006, p. 1) provides in its Article 37 that for
medicinal products designated as orphan medicinal products, if speci-
fied criteria in the paediatric Regulation are met, the ten-year period
referred to in Article 8(1) of Regulation (EC) No 141/2000 shall be
extended to twelve years (two-year extension as reward for compli-
ance with paediatric investigation plan).

(7) For products falling under Article 37 of the above-cited paediatric
Regulation the reduced period under Article 8(2) of Regulation (EC)
No 141/2000 will be equally six years; Article 37 of the paediatric
Regulation only affects the calculation of the period referred to in
Article 8(1) of Regulation (EC) No 141/2000.

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Article 8(5) provides the legal basis for the Commission to draw
up detailed guidelines for the application of Article 8. This
guideline fulfils part of that requirement as it relates specifically
to Article 8(2).

3. GENERAL

PRINCIPLES

FOR
ARTICLE 8(2)

THE

REVIEW UNDER

The review procedure of Article 8(2) is triggered by information
received from a Member State relating to a specific designation
of an orphan medicinal product. The initiation of the procedure
established in Article 8(2) is not intended to be systematic for
all orphan designated products; on the contrary, Member States
should only inform the European Medicines Agency (hereinafter
‘the Agency’) if they have sufficient indications suggesting that
the designation criteria are no longer met;
in that case, they
have to do so. The review procedure under Article 8(2) is there-
fore expected to be the exception.

If and when the procedure is triggered by a Member State, an
assessment will be carried out within the Agency by the
Committee on Orphan Medicinal Products (‘COMP’), according
to the procedure laid down in Article 5(4) to 5(8) of Regulation
(EC) No 141/2000. COMP will provide an opinion as to
whether
the market exclusivity should be maintained or
reduced. For a given product, all authorised therapeutic indica-
tions falling within the scope of the same orphan designation
will be assessed in the same procedure.

The review of market exclusivity by COMP will be based, in a
first step, on the same set of criteria on which designation was
granted according to Article 3 of the same Regulation. The
period of market exclusivity will not be reduced to six years, if
at the end of the fifth year the original designation criteria are
still met. If the original criteria are no longer met, COMP will
also review, in a second step of its assessment, the situation of
the product concerned as regards the other designation criteria
of Article 3(1) of Regulation (EC) No 141/2000.

The guidance provided in Section 5 below should be read
jointly with the existing provisions and guidance as regards the
factors that should be considered when initially assessing the
designation criteria and the documentation relevant
to that
effect, and when re-evaluating the designation criteria before
granting marketing authorisation. These factors and documenta-
tion will apply by analogy at the time of the review of the
period of market exclusivity. In particular, they are laid down in
the following texts:

— Regulation (EC) No 847/2000 and the Commission commu-
nication of 2003, referred to above, which contain various
rules on the evaluation of the designation criteria, and

— the Guideline on the format and content of applications for
designation as orphan medicinal products and on the
transfer of designation from one sponsor to another (1),
which contains practical advice on how to compile the
documents
the designation
criteria.

substantiating fulfilment of

(1) Available at:

http://ec.europa.eu/enterprise/pharmaceuticals/orphanmp/index.htm
and regularly updated

After receipt of the opinion, the Commission will adopt a deci-
sion, according to the procedure laid down in Article 5(8) of
Regulation (EC) No 141/2000. Where the decision is to reduce
the period of market exclusivity, the product concerned will be
removed from the Community Register of Orphan Medicinal
Products, in accordance with Article 5(12) of Regulation (EC)
No 141/2000.

The evaluation of the product by the Agency and the Commis-
sion will generally take place at the end of the fifth year from
marketing authorisation in all Member States. If as a result of
such evaluation the orphan status of the product is maintained,
no other revision is foreseen between the sixth year and the end
of the period of market exclusivity.

4. INFORMATION BY A MEMBER STATE

Article 8(2) of Regulation (EC) No 141/2000 establishes that a
Member State shall inform the Agency that at least one of the
designation criteria, on the basis of which market exclusivity
was granted, may not be met.

According to Article 8(2) of Regulation (EC) No 141/2000, the
period of market exclusivity may be reduced when appropriate
evidence is established at the end of the fifth year of market exclu-
sivity. To allow for the handling of Member States' information
within this time frame, Member States are advised to submit
this information by the end of the fourth year of market exclu-
sivity.

The Member State in question should provide the rationale for
its doubts and include appropriate data justifying why at least
one of the original designation criteria of the orphan medicinal
product concerned may no longer be met. In preparing its infor-
mation to the Agency, the Member State may use data which
supported the initial designation, held by the Agency.

5. ASSESSMENT BY THE AGENCY

Once the Agency has received information by one or more
Member State(s) according to Article 8(2) of Regulation (EC)
No 141/2000, the Agency will inform the Commission and the
marketing authorisation holder before the assessment procedure
is initiated. The market authorisation holder shall be provided
with the Member State's reasons why at least one of the designa-
tion criteria on the basis of which market exclusivity was
granted may not be met; he shall be given the opportunity to
submit its views and appropriate data in writing, and may be
invited to a hearing in front of COMP.

COMP will issue an opinion as a result of the assessment, justi-
fying whether or not the orphan status of the product should
be maintained. In its assessment, COMP will review the relevant
designation criteria based on the evidence available to it, in par-
ticular provided by the sponsor and the referring Member State.
If the available evidence is insufficient to establish with reason-
able confidence whether or not the designation criteria continue
to be met, COMP will recommend that the period of market
exclusivity is not reduced.

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The assessment will be done in two steps. In a first step (see
under 5.1 below), COMP will review the initial designation
criteria. If the initial designation criteria are still met, COMP will
the period of market
adopt an opinion recommending that
exclusivity is not reduced.

due to improved survival as a result of other advances in the
management of the condition not directly related to the product
or due to increased incidence would need to be taken into
consideration.

If the original criteria are no longer met, step two will be
receiving the necessary
performed (see under 5.2): after
information from the sponsor COMP will review whether the
other designation criteria of Article 3(1) of Regulation (EC)
No 141/2000 are met.

If the other designation criteria of Article 3(1) of Regulation
(EC) No 141/2000 are fulfilled, COMP will adopt an opinion
recommending that
the period of market exclusivity is not
reduced.

If none of the criteria for designation under Article 3(1) of
Regulation (EC) No 141/2000 are met, COMP will adopt an
opinion which may recommend that the period of market exclu-
sivity shall be reduced.

5.1. First step

COMP will review the initial designation criteria, i.e. the criterion
under Article 3(1)(a) and the criterion under Article 3(1)(b) of
Regulation (EC) No 141/2000 which led to the designation as
an orphan medicinal product.

5.1.1. Alternative criteria of Article 3(1)(a) of Regulation (EC)

No 141/2000

5.1.1.1. Products initially designated on the basis of

prevalence

For products initially designated on the basis of the prevalence
criterion of Article 3(1)(a),
the Agency's
assessment will include an evaluation of the prevalence of the
orphan condition at the time of the review of market exclu-
sivity.

first subparagraph,

The prevalence in the Community will be calculated for the
designated orphan condition under review following the same
standards as the ones used at the moment of designation.

The sponsor will be requested to provide a critical review of
possible changes in the estimated prevalence of the condition,
including a discussion on the impact of the product on the
prevalence in comparison with the natural development of the
prevalence of the condition. The prevalence estimate may in
time either because the prevalence was
principle rise over
to
previously underestimated
increasing awareness of
the condition) or because the true
prevalence of the condition has risen (e.g. increasing incidence
or increased survival).

(e.g. better

estimates

due

5.1.1.2. Products initially designated on the basis of

insuffici ent retur n on investment

For products initially designated on the basis of the insufficient
return on investment criterion of Article 3(1)(a), second sub-
paragraph, the Agency will use the same methodology at the
time of the review of market exclusivity as the one used at the
moment of designation.

The test used under Article 3(1)(a) at the time of designation is
whether ‘without incentives it is unlikely that the marketing of the
medicinal product in the Community would generate sufficient
return to justify the necessary investment’ (emphasis added). The
criterion is thus based on a prognosis: the unlikelihood that the
expected return would justify the required investment. The test
is fulfilled,
it appears unlikely that a sponsor would be
prepared to make the investment as the expected return would
not be sufficient to compensate for the sponsor's risks.

if

The corresponding test at the time of the review of market
exclusivity would use the same principles. Therefore,
the
criterion would still be fulfilled if the marketing of the medicinal
product in the Community, without the incentive, would not
generate sufficient return on investment to balance the risks
already taken or still
If, after
subtraction of the financial benefits gained as a result of the
incentives under the Regulation, the return on investment is
insufficient, market exclusivity will not be reduced.

to be taken by the sponsor.

5.1.2. Alternative criteria of Article 3(1)(b) of Regulation (EC)

No 141/2000

For the criteria of Article 3(1)(b) — inexistence of a satisfactory
method or significant benefit — the Agency will
take into
account any changes affecting the treatment, prevention or
diagnosis of patients within the designated condition since the
date of the marketing authorisation.

The sponsor may be requested to provide a critical review of its
product at the time of the review of market exclusivity. The
critical review will include any available data, for instance:

— results of any comparative studies performed,

— a comprehensive and balanced bibliographic review,

— marketing studies, or

— patients' surveys.

A prolongation of patient survival attributable to the effect of
the drug would not be used as a reason to reduce market exclu-
sivity. However, an increase in the prevalence of the condition

sponsors will not be required to generate new
However,
comparative data against another treatment/treatment method
that has become available since a marketing authorisation was
granted for the designated product.

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5.1.2.1. Products initially designated on the basis of

5.2.2. Alternative criteria of Article 3(1)(b) of Regulation (EC)

inexistence of a satisfactory method

No 141/2000

For products initially designated on the basis of inexistence of a
satisfactory method (Article 3(1)(b),
information
which may be requested from the sponsor includes a critical
review of the place of the product in the therapeutic, diagnostic
or prophylactic management of patients within the authorised
therapeutic indication at the time of the review of market exclu-
sivity.

first part),

5.1.2.2. Products initially designated on the basis of

signif icant benef it

For products initially designated on the basis of significant
benefit (Article 3(1)(b), second part), information which may be
requested from the sponsor includes a critical review of the
maintenance of the significant benefit of the product in the
designated condition, in comparison with methods of treatment,
diagnosis or prophylaxis at the time of the review of market
exclusivity.

5.1.3. COMP opinion

If COMP comes to the conclusion that the initial designation
criteria are still met, it will recommend that the period of market
exclusivity is not reduced.

5.2. Second step

If COMP is of the opinion that the initial criteria for designation
are no longer met, it will provide the sponsor with an opportu-
nity to demonstrate that the market exclusivity can be main-
tained based on the other designation criteria of Article 3(1) of
Regulation (EC) No 141/2000. The sponsor will be requested to
provide the Agency with the information necessary for that
purpose.

5.2.1. Alternative criteria of Article 3(1)(a) of Regulation (EC)

No 141/2000

Where the initial designation was based on prevalence and it is
concluded that this criterion is no longer met, COMP will assess
the return on investment of the product at the time of the
review of market exclusivity.

On the other hand, where the initial designation was based on
return on investment and it is concluded that this criterion is
no longer met, COMP will assess the prevalence of the product
at the time of the review of market exclusivity.

Where the initial designation was based on the inexistence of a
satisfactory method and it is concluded that this criterion is no
longer fulfilled, COMP will assess the significant benefit of the
product at the time of the review of market exclusivity.

On the other hand, where the initial designation was based on
significant benefit, and it is concluded that this criterion is no
longer fulfilled, there would normally not be an alternative test
available. However, COMP would assess the inexistence of a
satisfactory method at the time of the review of market exclu-
sivity in exceptional cases; this could for instance be the case if
a method existing at the time of designation had in the mean-
time disappeared.

5.2.3. COMP opinion

If the COMP assessment under step two shows that the alterna-
tive designation criteria of Article 3(1)(a) and Article 3(1)(b) are
met, COMP will adopt an opinion recommending that the period
of market exclusivity is not reduced.

If following the assessments in steps one and two it turns out
that neither the initial, nor the alternative designation criteria of
Article 3(1)(a) and Article 3(1)(b) are met, COMP will adopt an
opinion which may recommend that the period of market exclu-
the COMP, on
reduced. Relevant criteria for
sivity shall be
whether or not to recommend a reduction of market exclusivity,
would include the extent according to which a designation
criterion is not fulfilled. Furthermore, COMP should consider
insufficient profitability as an argument against the reduction of
market exclusivity.

6. DECISION BY THE EUROPEAN COMMISSION

The Commission will take a decision on whether market exclu-
the
sivity is to be maintained or reduced, on the basis of
opinion of COMP. According to Article 5(8) of Regulation (EC)
No 141/2000, this decision shall be adopted within 30 days of
receipt of the opinion.

According to Article 5(8) of Regulation (EC) No 141/2000, the
Commission may in exceptional circumstances adopt a decision
which is not in accordance with the opinion of COMP. In exer-
cising this discretion, the Commission will take into account the
specific circumstances of the product concerned in the light of
the Regulation's key objectives, i.e. improving the availability of
orphan medicinal products and ensuring appropriate and effec-
tive incentives for research and development in this sector.