Guideline on aspects of the application of Article 8(1) and (3) of Regulation (EC) No 141/2000: Assessing similarity of medicinal products versus authorised orphan medicinal products benefiting from market exclusivity and applying derogations from that market exclusivity
Date: 2008-09-23
Institutions: Council of the European Union, European Parliament
Subjects: application of EU law, derogation from EU law, drugs classification, exclusive distribution agreement, market approval, medicinal product, pharmaceutical legislation

C 242/12

EN

Official Journal of the European Union

23.9.2008

Guideline on aspects of the application of Article 8(1) and (3) of Regulation (EC) No 141/2000:
Assessing similarity of medicinal products versus authorised orphan medicinal products benefiting
from market exclusivity and applying derogations from that market exclusivity

(2008/C 242/08)

1. INTRODUCTION

Paragraph 5 of Article 8 of Regulation (EC) No 141/2000
requires the Commission to draw up detailed guidelines for the
application of Article 8 of that Regulation. This guideline fulfils
part of that requirement, providing guidance on the application
of Articles 8(1) and 8(3) of that Regulation.

This guideline should be read in conjunction with:

— Regulation (EC) No 141/2000 of the European Parliament

and of the Council on orphan medicinal products,

— Commission Regulation (EC) No 847/2000 laying down the
provisions for implementation of the criteria for designation
of a medicinal product as an orphan medicinal product and
definitions of the concepts ‘similar medicinal product’ and
‘clinical superiority’,

— Communication from the Commission on Regulation (EC)
the
hereafter

the European Parliament and of

No 141/2000 of
Council
‘Commission Communication’.

on orphan medicinal

products (1),

According to Article 8(1) of Regulation (EC) No 141/2000,
where a marketing authorisation in respect of an orphan medic-
inal product is granted either by centralised procedure or in all
Members States, the Community and the Member States shall
not, for a period of 10 years, accept another application for a
marketing authorisation, or grant a marketing authorisation
or accept an application to extend an existing marketing
authorisation, for the same therapeutic indication, in respect of
a similar medicinal product (so-called 10 year market exclu-
sivity) (2). The scenarios ‘application for a marketing authorisa-
tion’ and ‘application to extend an existing marketing authorisa-
tion’ will hereafter be referred to together as ‘application for a
marketing authorisation’.

With regard to Article 8(1),
guidance on the following questions:

the present guideline provides

What are the relevant criteria for assessing similarity of a
medicinal product? See under Section 2 below.

What is the procedure used by the competent authorities for
assessing similarity? See under Section 3 below.

Article 8(3) of Regulation (EC) No 141/2000 describes three
types of derogations from the market exclusivity provided under
the original
Article 8(1) of
that Regulation:
the original
marketing authorisation holder;
marketing authorisation holder to supply sufficient quantities;
(c) the second medicinal product is safer, more effective or
otherwise clinically superior.

(a) consent of
inability of
(b)

(1) OJ C 178, 29.7.2003, p. 2.
(2) 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 that for medicinal products
designated as orphan medicinal products, if specified 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 (see Article 37 of that Regulation).

With regard to Article 8(3) of Regulation (EC) No 141/2000,
the present guideline provides guidance on the following ques-
tions:

What is the relevant procedure for assessing whether one of the
derogations applies? See Section 3 below.

2. GENERAL PRINCIPLES FOR ASSESSMENT OF SIMILARITY

Article 3 of Regulation (EC) No 847/2000 provides
following definitions:

the

— ‘similar medicinal product’ means a medicinal product
containing a similar active substance or substances as
contained in a currently authorised orphan medicinal
product, and which is intended for the same therapeutic
indication,

— ‘similar active substance’ means an identical active substance,
or an active substance with the same principal molecular
the same
structural features (but not necessarily all of
molecular
same
mechanism. Regulation (EC) No 847/2000 then provides
specific examples,

and which acts

features)

the

via

— ‘active substance’ means a substance with physiological or

pharmacological activity.

the assessment of

Based on the definitions set out in Article 3 of Regulation (EC)
No 847/2000,
similarity between two
medicinal products under Article 8 of Regulation (EC)
No 141/2000 takes into consideration principal molecular
structural features, mechanism of action and therapeutic indica-
tion. If significant differences exist within one or more of these
criteria, then the two products will be considered as not similar.
These three criteria are further explained below.

The International Non proprietary Names (INN) may provide
preliminary information in assessing the similarity of
the
molecular structural features and the mechanism of action. In
the
the names of pharmacologically-related
substances may show their relationship by using a common
‘suffix’/substem.

INN system,

2.1. Same principal molecular structural features

The following, general considerations should be taken into
account for the assessment of the molecular structural features
of the active substance (though for macromolecules, particularly
complex biological medicinal products, not
these
considerations may be appropriate).

all of

23.9.2008

EN

Official Journal of the European Union

C 242/13

The applicant should demonstrate the proposed structure of the
molecule as follows:

A pharmacological
target
channel, carrier or an intracellular coupling process.

is usually a receptor, enzyme,

— the evidence relating to the demonstration of structure
two-and three

should be summarised in unambiguous
dimensional graphical representations, whenever possible,

— where possible, the active substance should be described
IUPAC (1) or

precisely using systematic terminology, e.g.
CAS (2) nomenclature,

— where the active substances have a recommended INN
name, the World Health Organisation structures and reports
should be provided.

If any of the above information is not provided or not available,
a justification should be given.

features of

The principal molecular structural
the product
should be described, based on evidence and compared to those
of the authorised orphan medicinal product. It should be noted
that certain observed differences in structure may appear major
in the molecule's crystalline state (i.e. based on X-Ray data).
However, since molecules exert their biological action in solu-
tion, these differences seen in the crystalline state may not be
relevant for the assessment of similarity.

Software programs may be used to measure the degree of struc-
tural similarity between molecules; many of
them allowing
‘similarity searching’ to identify molecules having common or
similar molecular architectural features (2- or 3-dimensional).

2.2. Same mechanism of action

The mechanism of action of an active substance is the func-
tional description of the interaction of the substance with a
pharmacological target that elicits a pharmacodynamic effect.
In case the mechanism of action is not fully known, it will be
for the applicant to demonstrate that the two active substances
do not act via the same mechanisms.

Two active substances may only be considered to have the same
mechanism of action, provided that both share the same phar-
macological target and pharmacodynamic effect.

Factors not relevant to the mechanism of action are differences
between two substances in terms of:

— mode of administration,

— pharmacokinetic properties,

— potency, or

— tissue distribution of the target.

A prodrug is considered to have the same mechanism of action
as its active metabolite.

(1) IUPAC stands for International Union of Pure and Applied Chemistry.
(2) CAS stands for Chemical Abstracts Service, which is a division of the

American Chemical Society.

is the action of

the active
The pharmacodynamic effect
substance on the body (e.g. bradycardia). For the purpose of
assessing similarity of the second product with an authorised
orphan medicinal product, the pharmacodynamic effect relevant
to the ‘mechanism of action’ is the primary pharmacodynamic
effect of the active substance, which determines the therapeutic
indication.

Two substances with the same pharmacological target may elicit
a different pharmacodynamic effect depending on the location
of the target, or depending on whether the target is activated or
inhibited.

Two active substances with the same pharmacodynamic effect
may act at different pharmacological targets. In case these two
active substances act at multiple targets (including subtypes of
the same receptor) and share at least one common target, it should
be considered whether
the common target(s) explain the
primary pharmacodynamic effects which determine the thera-
peutic indication (3).

2.3. Same therapeutic indication

The therapeutic indication of an orphan medicinal product is
determined by the marketing authorisation and has to fall
within the scope of the (possibly broader) designated orphan
condition, cf. Section C.1 of the Commission Communication.

If an orphan medicinal product has been granted a marketing
authorisation for an indication which is a subset of the desig-
nated condition, an application for marketing authorisation of a
second product, which claims to cover a different therapeutic
the same designated
indication, and thus another subset of
orphan condition, will have to establish that
the difference
between the two subsets is clinically meaningful. If there is an
overlap of the target populations of two allegedly different ther-
apeutic indications, the second applicant would have to provide
the authority with an estimate of its extent. The extent of the
overlap will be a relevant factor for the authority to establish
whether the claim for two different therapeutic indications can
be upheld.

3. PROCEDURE FOR ASSESSING SIMILARITY AND FOR

APPLYING THE DEROGATIONS IN ARTICLE 8(3)

3.1. Competent authority

According to Article 8(1) of Regulation (EC) No 141/2000, the
Community and the Member States shall not, for a period of
10 years, accept a marketing authorisation application for a
medicinal product
(hereafter also ‘second product’) which is
similar to an authorised orphan medicinal product (hereafter
also ‘first product’).

(3) For example: atenolol and propranolol would be considered to have the
same mechanism of action regarding their indication in hypertension,
even if they have different selectivity and potency at β1-receptor and
β2-receptor levels. On the other hand, for example carvedilol and meto-
prolol would not be considered to have the same mechanism: although
they share β-receptor blocking activity, their mechanisms of action
differ for the treatment of severe congestive heart failure due to the
additional α-receptor blocking activity of carvedilol.

C 242/14

EN

Official Journal of the European Union

23.9.2008

The competent authority for providing the assessment of simi-
larity, and if applicable the fulfilment of the criteria for one of
the derogations set out in Article 8(3)
(‘competent assessing
body’) is to be determined depending on the route of marketing
authorisation of
the second product. The second medicinal
product may be authorised either nationally (non-orphan
product (1)) or centrally (either orphan or non-orphan product).

‘non’ similarity, addressing the three criteria for assessing simi-
larity:

— molecular structural features,

— mechanism of action, and

— therapeutic indication.

For centralised marketing authorisation applications of a
second product to be compared with an authorised orphan
medicinal product, the competent assessing body is the Agency.

Particular emphasis should be made on the explanation of the
first two criteria. If the applicant claims that the two products
are not similar, he should provide reasons to support this claim.

For applications filed through National, Mutual Recognition
or Decentralised Procedures, the competent assessing body/ies
is/are the national competent authority/ies concerned.

3.3.2. Derogations

3.2. Validation

for a marketing authorisation of a (‘second’)
The applicant
product potentially similar to an authorised orphan medicinal
(‘first’) product will have to provide appropriate documentation
on his position regarding similarity of the second product with
the first product and, if relevant, a justification that one of the
derogations set out in Article 8(3) applies (see Section 3.3 ‘infor-
mation to be submitted by the applicant’ and Section 3.4 ‘identi-
fication of relevant products …’).

The application for the second product will be validated by the
competent assessing body if this documentation/justification is
contained in the application. Applicants should be aware that
validation implies a formal check (all relevant documents have
been submitted) but does not give any indication as to the
outcome of the material assessment of their application.

If the application concerns a generic medicinal product, simi-
larity is assumed. Consequently, the application cannot be vali-
dated before the end of the period of market exclusivity unless
justification is provided to support one of the derogations laid
down in Article 8(3).

3.3. Information to be submitted by the applicant

that one of

To support
Article 8(3), paragraphs (a)
applies,
module 1.7.2, as applicable:

the derogations laid down in
the same Regulation
to (c) of
the following information should be submitted in

3.3.2.1. Ar ticle 8(3)(a)

If the holder of the marketing authorisation for the original
orphan medicinal product has given his consent to the second
applicant:

A signed letter from the holder of authorised orphan medicinal
product confirming his/her consent for the second applicant to
file an application for marketing authorisation,
in accordance
with Article 8(3)(a) of Regulation (EC) No 141/2000.

3.3.2.2. Ar ticle 8(3)(b)

If the holder of the marketing authorisation for the original
orphan medicinal product is unable to supply sufficient quan-
tities of the medicinal product:

the authorised orphan
A report describing why supply of
medicinal product is deemed to be insufficient, in accordance
with Article 8(3)(b) of Regulation (EC) No 141/2000.

Information to address potential
and, where
applicable, to justify that one of the derogations laid down in
Article 8(3) of Regulation (EC) No 141/2000 applies should be
submitted in module 1.7 of
the application for marketing
authorisation.

‘similarity’

The report should include details of the supply problem and an
explanation as to why patients' needs in the orphan indication
are not being met. All claims should be substantiated by qualita-
tive and quantitative references.

3.3.1. Similarity

3.3.2.3. Ar ticle 8(3)(c)

For similarity, a report should be included in module 1.7.1
comparing the product with authorised orphan medicinal
products in the context of similarity as defined in Article 3(3) of
Regulation (EC) No 847/2000 and concluding on similarity or

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

(1) As of 20 November 2005, designated orphan medicinal products may
only be authorised via the centralised authorisation procedure
(Article 3(1) of Regulation (EC) No 726/2004). Thus, a second product
can only be authorised nationally, if it is not an orphan medicinal
product.

is
A critical report which justifies why the second product
deemed to be ‘clinically superior’
to the authorised orphan
medicinal product, in accordance with Article 8(3)(c) of Regu-
lation (EC) No 141/2000.

23.9.2008

EN

Official Journal of the European Union

C 242/15

The report should include a comparison of the two products in
the context of ‘clinical superiority’ as defined in Article 3(3)(d)
of Regulation (EC) No 847/2000, with particular reference to:

The competent assessing body should assess ‘similarity’ and, if
applicable the fulfilment of the derogation ‘clinical superiority’
in parallel with the evaluation of the quality/safety/efficacy of
the medicinal product.

— the results of clinical studies,

— the scientific literature.

3.4. Identification of

relevant products
similarity check

to perform

For any application for marketing authorisation, the competent
assessing body should check which authorised orphan medicinal
products need to be taken into consideration for an assessment
of possible similarity. This check should first be performed
prior to validating the application.

If a competent assessing body identifies a possible similarity
issue not addressed by the applicant before validation, the appli-
cant will be asked to complete the application with information
on ‘similarity’ and, if applicable, on one of the derogations in
Article 8(3). Validation of
the application will only proceed
once the applicant has submitted either a report justifying the
lack of similarity or information justifying one of the deroga-
tions in Article 8(3), see above under 3.3 ‘information to be
submitted by the applicant’.

As considerable time may elapse between validation of an appli-
cation and adoption of the opinion/granting of a marketing
authorisation, the competent assessing body should repeat its
check of possibly similar orphan medicinal products prior to
the granting/amendment of the marketing authorisation: new
orphan medicinal products may have been authorised for the
same condition in the meantime.

For the centralised procedure, the Agency will repeat its check
for possibly similar orphan medicinal products before the
Committee for Medicinal Products for Human Use (CHMP)
issues a positive opinion. Where additional possible similarity
issues are identified,
the applicant will be asked to submit
further relevant documentation on similarity (and, if necessary,
documentation to support
the derogations in
Article 8(3) applies). The ‘procedural clock’ will be stopped until
this documentation is submitted.

that one of

Should a new issue of possible similarity be identified during
the procedure at the level of the European Commission, during
the preparation of a marketing authorisation decision, the latter
may refer the CHMP opinion back to the Agency for further
evaluation.

3.5. Procedure for assessing similarity and for applying the

derogation based on ‘clinical superiority’

Following identification of the relevant products to perform the
the competent assessing body will
product similarity check,
initiate the procedure for assessing similarity and, if its opinion
on similarity is positive, the procedure for assessing whether a
derogation under Article 8(3) is fulfilled.

Should the competent assessing body come, only during the
quality/safety/efficacy evaluation, to the conclusion that there is
similarity between the product under evaluation and an
authorised orphan medicinal product,
the applicant will be
requested at that time to submit a justification that one of the
derogations in Article 8(3) is fulfilled.

3.5.1. Centralised procedure

The CHMP opinion on ‘similarity’ and, where applicable on
‘clinical superiority’ will be part of
the overall opinion on
quality/safety/efficacy. Where clinical superiority is assessed, the
basis for clinical superiority will be described in the European
Public Assessment Report.

Re-examination of C HMP opinion

Once the CHMP has concluded its assessment of similarity and,
if applicable, of the fulfilment of the criteria for the derogation
‘clinical superiority’, the applicant may ask for a re-examination
of the CHMP Opinion according to the principles set out in
Article 9(2) of Regulation (EC) No 726/2004.

Scientific advice or protocol assistance on similar ity
and clinical super ior ity

Applicants seeking to develop a product where an issue on simi-
larity with an orphan medicinal product might arise can request
Scientific Advice (or Protocol Assistance) from the CHMP. In its
request for advice, the applicant will have to document its posi-
tion regarding similarity and, if relevant, provide a justification
for one of the derogations.

If the applicant intends to rely on the derogation of clinical
superiority, Scientific Advice or Protocol Assistance can be
requested, and is recommended, on the appropriateness of the
study(ies) intending to demonstrate clinical superiority.

3.5.2. National, Mutual Recognition and Decentralised Procedures

It is highly recommended that the relevant national competent
assessing body in a national, mutual recognition or decentralised
procedure informs the Agency as soon as a potential similarity
issue with an authorised orphan medicinal product is detected.
In order to ensure consistency of the assessment of similarity
and clinical superiority throughout the Community, it would be
advisable to have a consultation process between the Agency's
CHMP and the national authority.

In all cases, the Agency should be informed of the national
authority's conclusions on similarity and, if applicable, clinical
superiority.

C 242/16

EN

Official Journal of the European Union

23.9.2008

3.6. Procedure for applying the derogation based on

‘inability to supply sufficient quantities’

parallel, having been received by the Agency at the same time,
the following scenarios may arise:

For the derogation set out in Article 8(3)(b) of Regulation (EC)
No 141/2000 — the holder of the marketing authorisation of
the original orphan medicinal product is unable to supply suffi-
cient quantities of the medicinal product — the applicant of the
second product will have to provide the competent assessing
body with a report supporting this derogation (see above
under 3.3 ‘information to be submitted by the applicant’).

the original product,

The competent assessing body should circulate the applicant's
report to (other) Member States for comments. The competent
assessing body should also liaise with the marketing authorisa-
tion holder of
inviting him to submit
comments in writing. The competent assessing body should
issue a position on the fulfilment of the criteria for derogation,
taking into account the applicant's report as well as comments
received from Member States and the marketing authorisation
holder. If the derogation is assessed in the framework of the
centralised procedure, this position shall be part of the CHMP
opinion.

3.7. Parallel assessment of two applications for the same

orphan condition

3.7.1. Centralised procedure

In case two procedures for granting marketing authorisations
for possibly similar orphan medicinal products are running in

In the very exceptional case where marketing authorisation appli-
cations for the same orphan indication are received at the same
time and, being handled in accordance with the relevant provi-
sions of the pharmaceutical legislation, the authorisation proce-
dures remain in parallel, an opinion on similarity of the two
products will not be necessary.

On the other hand, where for these simultaneous marketing
authorisation applications, based on the examination of each
application on its own merits, the two authorisation procedures
do not remain in parallel, an opinion on similarity will be neces-
sary: as soon as one of the products with orphan status obtains
marketing authorisation, the applicant for the other (second)
product will be informed that a marketing authorisation for a
possibly similar orphan medicinal product has been granted. A
report on ‘similarity’ and, if applicable a justification for one of
the derogations in Article 8(3) will be requested from this appli-
cant.

3.7.2 National, Mutual Recognition and Decentralised Procedures

In case a medicinal product has been designated as an orphan
medicinal product and its marketing authorisation is under
assessment, but has not yet been granted by the European
Commission, a parallel assessment of a possibly similar
(non-orphan (1)) medicinal product can occur by a national
authority. As there is no authorised orphan medicinal product
yet, the marketing authorisation may be granted (without an
opinion of similarity).

(1) See under 3.1 above: since 20 November 2005, designated orphan
medicinal products may only be authorised via the centralised authori-
sation procedure.