CELEX: 62007CJ0527
Reference for a preliminary ruling
Directive 2001/83/EC
Medicinal products for human use
Marketing authorisation
Grounds of refusal
Generic medicinal products
Concept of ‘reference medicinal product’

This reference for a preliminary ruling concerns the interpretation of Article 10 of Directive 2001/83/EC of the European
Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ 2001
L 311, p. 67), as amended by Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 (OJ 2004
L 136, p. 34) (‘Directive 2001/83’).
The reference was made in the course of proceedings between Generics (UK) Ltd (‘Generics’), a company incorporated under English
law which distributes medicinal products, and the Licensing Authority, which is the competent authority in the United Kingdom
for issuing marketing authorisations, concerning the lawfulness of the Licensing Authority’s decision refusing Generics’ application
for marketing authorisation for the generic medicinal product galantamine.

The legal framework
According to recital 1 in the preamble to Directive 2001/83, that directive codified and assembled in a single text the directives
on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products for
human use, which included Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by law,
regulation or administrative action relating to medicinal products (OJ English Special Edition 1965-1966(I) p. 24), as amended
by Council Directive 93/39/EEC of 14 June 1993 (OJ 1993 L 214, p. 22) (‘Directive 65/65’), Council Directive 75/318/EEC of
20 May 1975 on the approximation of the laws of Member States relating to analytical, pharmaco-toxicological and clinical
standards and protocols in respect of the testing of proprietary medicinal products (OJ 1975 L 147, p. 1), as amended by Commission
Directive 1999/83/EC of 8 September 1999 (OJ 1999 L 243, p. 9), and Council Directive 75/319/EEC of 20 May 1975 on the approximation
of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products (OJ 1975 L
147, p. 13), as amended by Commission Directive 2000/38/EC of 5 June 2000 (OJ 2000 L 139, p. 28) (‘Directive 75/319’).
Recitals 2, 4, 5 and 10 in the preamble to Directive 2001/83 state:
‘(2)      The essential aim of any rules governing the production, distribution and use of medicinal products must be to safeguard public
health.
…
(4)      Trade in medicinal products within the Community is hindered by disparities between certain national provisions, in particular
between provisions relating to medicinal products (excluding substances or combinations of substances which are foods, animal
feeding-stuffs or toilet preparations), and such disparities directly affect the functioning of the internal market.
(5)      Such hindrances must accordingly be removed; whereas this entails approximation of the relevant provisions.
…
(10)      However, there are reasons of public policy for not conducting repetitive tests on humans or animals without over-riding cause.’
Article 6(1) of that directive provides:
‘No medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued by the
competent authorities of that Member State in accordance with this Directive or an authorisation has been granted in accordance
with [Council] Regulation (EEC) No 2309/93 [of 22 July 1993 laying down Community procedures for the authorisation and supervision
of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products
(OJ 1993 L 214, p. 1)].’
According to Article 88 of Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying
down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing
a European Medicines Agency (OJ 2004 L 136, p. 1), Regulation No 2309/93 is repealed and references to that regulation are
to be construed as references to Regulation No 726/2004.
Article 8 of Directive 2001/83 corresponds, in essence, to Article 4 of Directive 65/65. Article 8(3)(i) of Directive 2001/83
provides:
‘The application [for marketing authorisation] shall be accompanied by the following particulars and documents, submitted
in accordance with Annex I:
…
(i)      Results of:
–        pharmaceutical (physico-chemical, biological or microbiological) tests,
–        pre-clinical (toxicological and pharmacological) tests,
–        clinical trials;
…’
Article 10(1) and (2) of Directive 2001/83 states:
‘1.      By way of derogation from Article 8(3)(i), and without prejudice to the law relating to the protection of industrial and commercial
property, the applicant shall not be required to provide the results of pre-clinical tests and of clinical trials if he can
demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised under
Article 6 for not less than eight years in a Member State or in the Community [“the period of protection”].
…
2.      For the purposes of this Article:
(a)      “reference medicinal product” shall mean a medicinal product authorised under Article 6, in accordance with the provisions
of Article 8;
(b)      “generic medicinal product” shall mean a medicinal product which has the same qualitative and quantitative composition in
active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference
medicinal product has been demonstrated by appropriate bioavailability studies. …’
According to Articles 2 and 3 of Directive 2004/27, where the application for authorisation was made before 30 October 2005,
the applicable period of protection is that laid down in Article 10 of Directive 2001/83 prior to its amendment by Directive
2004/27. The original wording of Article 10 provided that the period of protection was to be not less than 6 years, but that
it was open to each Member State to extend that period of protection up to 10 years.
Article 28(1) of Directive 2001/83 states:
‘With a view to the granting of a marketing authorisation for a medicinal product in more than one Member State, an applicant
shall submit an application based on an identical dossier in these Member States. The dossier shall contain the information
and documents referred to in Articles 8, 10, 10a, 10b, 10c and 11. The documents submitted shall include a list of Member
States concerned by the application.
The applicant shall request one Member State to act as “reference Member State” and to prepare an assessment report on the
medicinal product in accordance with paragraphs 2 or 3.’
According to the Agreement on the European Economic Area of 2 May 1992 (OJ 1994 L 1, p. 3), to which the Republic of Austria
was a party before its accession to the European Union, Directive 65/65 and Directive 75/319 were applicable in Austria from
1 January 1994.

The dispute in the main proceedings and the questions referred for a preliminary ruling
In 1963, the competent Austrian authorities granted to Waldheim, in accordance with the Austrian law in force at the time,
marketing authorisation for the medicinal product galantamine, under the brand name ‘Nivalin,’ for the treatment of poliomyelitis.
Although it appears that that authorisation for Nivalin was modified in 1995, in accordance with the applicable Community
law, to include its experimental use in the treatment of Alzheimer’s disease and, subsequently, to include ‘symptomatic treatment’
of that illness, it is not in dispute that the original dossier, on the basis of which the marketing of Nivalin was authorised,
was – for its part – never updated in accordance with the requirements of Directive 65/65 and Directive 75/319, now applicable
in Austria.
Waldheim withdrew Nivalin from the market in 2001.
Meanwhile, following the conclusion of cooperation agreements with Waldheim, Janssen-Cilag AB submitted to the Swedish competent
authorities, pursuant to Article 4 of Directive 65/65 (now Article 8 of Directive 2001/83), a full application for marketing
authorisation for galantamine, under the brand name ‘Reminyl’, for the treatment of Alzeiheimer’s disease. After having obtained
that authorisation on 1 March 2000, Janssen‑Cilag AB also obtained marketing authorisation for Reminyl in Austria on 22 August
2000.
In the United Kingdom, Shire Pharmaceuticals Ltd has been the holder of a marketing authorisation for Reminyl since 14 September
2000.
On 14 December 2005, in the context of a decentralised procedure pursuant to Article 28(1) of Directive 2001/83, Generics
submitted an application to the Licensing Authority for marketing authorisation for a generic of galantamine for the British
market. The United Kingdom of Great Britain and Northern Ireland was designated as the reference Member State. Simultaneous
applications were lodged in 17 other Member States.
That application was submitted on the basis of the generic product exception in Article 10(1) of Directive 2001/83. Nivalin
was specified as the reference medicinal product authorised for a period of not less than 10 years in the European Economic
Area (‘EEA’). The application also mentioned the marketing authorisation obtained in the United Kingdom by Shire Pharmaceuticals
Ltd for Reminyl, designated as the reference medicinal product in the United Kingdom, and as the product used for the bioequivalence
study necessary to demonstrate that the Generics product was, in fact, a generic of Nivalin/Reminyl.
The Licensing Authority rejected Generics’ application. It considered that Nivalin, covered by the authorisation issued in
Austria, could not be used as the reference medicinal product for an application for marketing authorisation for a generic
medicinal product for the purposes of Article 10(1) of Directive 2001/83, since its dossier had not been updated since 1 January
1994 to comply with the requirements of the Community legislation which had become applicable in Austria following the entry
into force of the EEA Agreement. As regards Reminyl, the 10-year period of protection referred to in Article 10 of Directive
2001/83, in its original version, had not yet expired and therefore the authorisation could not be granted on that basis.
Generics therefore challenged the Licensing Authority’s decision to reject its application before the High Court of Justice
of England and Wales, Queen’s Bench Division (Administrative Court), which decided to stay proceedings and to refer the following
questions to the Court of Justice for a preliminary ruling:
‘(1)      Where a medicinal product falling outside the scope of the Annex to Regulation [No] 2309/93 has been placed on the market
in a Member State ([Republic of] Austria) under its national authorisation procedure prior to the accession of that Member
State to the EEA or the [European Community] and:
–        that Member State has subsequently acceded to the EEA and then the [European Community], and as part of the conditions of
its accession it has transposed into its national law the authorisation provisions of Directive 65/65 (now Directive 2001/83)
[on marketing authorisation for medicinal products for human use], no transitional provisions applying in this respect;
–        the product in question has remained on the market in that Member State for some years after its accession to the EEA and
the [European Community];
–        following the accession of that Member State to the EEA and the [European Community], the marketing authorisation for the
product in question has been varied by adding a new indication, and the variation was considered by the authorities of that
Member State to be consistent with the requirements of Community law;
–        the dossier of the product in question was not updated in accordance with Directive 65/65 (now Directive 2001/83) after that
Member State’s accession to the EEA and the [European Community]; and
–        a product containing the same active ingredient has subsequently been authorised under Article 6 of Directive 2001/83 and
placed on the market in the [European Community];
is the medicinal product to be considered to be a “reference medicinal product which is or has been authorised under Article
6 … in a Member State” within the meaning of Article 10(1) of Directive 2001/83 and, if so, which of the above conditions
is/are decisive in this respect?
(2)      In circumstances where the competent authority of a reference Member State erroneously refuses an application for a marketing
authorisation made under Article 10(1) of Directive 2001/83 in the context of the decentralised procedure provided for in
that Directive, on the ground that the medicinal product referred to in Question 1 above was not a “reference medicinal product”
within the meaning of Article 10(1), what guidance, if any, does the Court of Justice think it appropriate to provide as to
which circumstances the national court ought to take into consideration when it comes to determine whether the breach of Community
law is a sufficiently serious breach within the meaning of the judgment in [Joined Cases C-46/93 and C‑48/93]
Brasserie du Pêcheur and Factortame
[1996] [ECR I-1029]?’

The questions referred

The first question
By its first question, the referring court asks, in essence, whether a medicinal product, such as Nivalin in the main proceedings,
which falls outside the scope of Regulation No 726/2004, and the placing of which on the market in a Member State was not
authorised in accordance with Directive 2001/83, can nevertheless be considered to be a reference medicinal product within
the meaning of Article 10(2)(a) of that directive.
In order to reply to that question, it should be recalled, at the outset, that the objective of the obligation on applicants
seeking marketing authorisation for a medicinal product, to attach to the application the results of toxicological and pharmacological
tests, and clinical trials, referred to in Article 8(3)(i) of Directive 2001/83, is to provide proof of the safety and efficacy
of a medicinal product (see, to that effect, Case C‑440/93
Scotia Pharmaceuticals
[1995] ECR I‑2851, paragraph 17, and Case C‑368/96
Generics (UK)  and Others
[1998] ECR I‑7967, paragraph 23).
It should also be borne in mind that the abridged procedure established by Article 10 of that directive – which relieves applicants
seeking marketing authorisation for a generic of a reference medicinal product already authorised in accordance with that
directive from having to provide the results of the aforementioned tests and trials – has, inter alia, as its objective, as
is apparent from recital 10 in the preamble to Directive 2001/83, to avoid the repetition of tests on humans or animals where
not absolutely necessary (
Generics (UK) and Others
, paragraphs 4 and 71).
Having regard in particular to the fact that, as is stated in recital 2 in the preamble to Directive 2001/83, the essential
aim of any rules governing the production and distribution of medicinal products must be to safeguard public health, the concept
of a ‘reference medicinal product’, within the meaning of Article 10(2)(a) of that directive, cannot be interpreted in such
a way that that abridged procedure amounts to a relaxation of the requirements of safety and efficacy which must be met by
medicinal products (see, to that effect,
Scotia Pharmaceuticals
, paragraphs 17 and 22, and
Generics (UK) and Others
, paragraph 22).
Thus, in order to be able to grant a marketing authorisation for a generic medicinal product on the basis of the abridged
procedure, what matters is that all the particulars and documents relating to the reference medicinal product remain available
to the competent authority concerned by the application for authorisation (see, to that effect, Case C‑223/01
AstraZeneca
[2003] ECR I‑11809, paragraph 27).
If that were not the case, respect for the standards of safety and efficacy which medicinal products must satisfy would be,
contrary to the requirements of the case-law referred to in paragraph 24 of this judgment, severely compromised, to the extent
that the producers of generic products would be relieved of having to carry out the toxicological and pharmacological tests,
and clinical trials, normally required by Community legislation, even though there would be no evidence of the safety and
efficacy of the reference medicinal product in question.
In other words, it is only in the case where the competent authority has all the particulars and documents relating to the
reference medicinal product that Article 10(1) of Directive 2001/83 replaces the obligation on applicants for marketing authorisation
to provide results of the tests and trials referred to in Article 8(3)(i) of that directive with the obligation to demonstrate
that the medicinal product in question is so similar to that reference medicinal product, which already benefits from such
an authorisation, that it does not differ significantly from that product as regards safety and efficacy (see, to that effect,
Generics (UK) and Others
, paragraphs 23 and 24).
In that regard, Generics claims, in essence, that a medicinal product placed on the market in a Member State for a number
of years in accordance with an authorisation issued on the basis only of the national provisions of that Member State – which
were applicable before the transposition in that State of the Community legislation in that area – may be considered to be
a reference medicinal product within the meaning of Article 10(2)(a) of Directive 2001/83.
Such an interpretation of Community law is unfounded.
It is apparent both from the wording and from the broad logic of Directive 2001/83, in particular from Articles 6, 8 and 10,
that only those medicinal products benefiting from a marketing authorisation issued in accordance with that directive can
be considered to be reference medicinal products. Likewise, as regards medicinal products for which marketing authorisation
was sought prior to the entry into force of that directive, it is clear from the case-law that, in order to benefit from the
abridged procedure, the applicant must show that the reference medicinal product was authorised on the basis of the Community
law in force at the time of the application for marketing authorisation for the reference medicinal product (see, to that
effect,
AstraZeneca
, paragraph 23).
Furthermore, any other interpretation of that directive would run counter not only to the requirements of safety and efficacy
of the medicinal products and, therefore, the objective of safeguarding public health, but also to the purpose of Directive 65/65
and, subsequently, Directive 2001/83, which – as is apparent from, inter alia, recitals 4 and 5 in the preamble to Directive
2001/83 – is to approximate national laws in the area.
Specifically, to allow a medicinal product benefiting from an authorisation issued on the basis of national provisions alone
– as applicable in the Member State concerned before the transposition in that State of the aforementioned directives – to
be considered to be a reference medicinal product would amount, in fact, to authorising an exception to the rule, laid down
in particular in Article 6(1) of Directive 2001/83, that a medicinal product which has not been authorised in accordance with
Community law may not be placed on the market of a Member State. As the Advocate General pointed out in points 31 to 34 of
his Opinion, there is no provision of that directive which envisages the possibility of such an exception or supports the
finding that the mere placing on the market, even for a number of years, of a medicinal product which has not been the subject
of a marketing authorisation issued in accordance with Community law, can replace such authorisation.
It follows from the foregoing considerations that, in order that a medicinal product may be considered to be a reference medicinal
product, it must have been authorised in accordance with Community law before being placed on the market.
In the present circumstances, it is apparent from the file submitted to the Court that Nivalin has never been the subject
of an application for marketing authorisation containing the particulars and the documents referred to in Article 8 of Directive
2001/83 and that, therefore, authorisation for it to be placed on the market has never been given in accordance with the requirements
of that directive.
Likewise, it is not in dispute that Nivalin has also not been the subject of an application for marketing authorisation in
accordance with the Community legislation applicable prior to the entry into force of that directive.
In actual fact, the placing of Nivalin on the market in Austria was authorised only under the legislation in force in Austria
at the time of the granting of the authorisation, namely in 1963, as that authorisation was never updated in accordance with
Community law following the accession of the Republic of Austria to the EEA and then the European Union.
The answer to the first question therefore is that a medicinal product, such as Nivalin at issue in the main proceedings,
which falls outside the scope of Regulation No 726/2004, and the placing of which on the market in a Member State was not
authorised in accordance with the applicable Community law, cannot be considered to be a reference medicinal product within
the meaning of Article 10(2)(a) of Directive 2001/83.

The second question
In the light of the answer given to the first question referred for a preliminary ruling, it is not necessary to answer the
second question.

Costs
Since these proceedings are, for the parties to the main proceedings, a step in the action pending before the national court,
the decision on costs is a matter for that court. Costs incurred in submitting observations to the Court, other than the costs
of those parties, are not recoverable.
On those grounds, the Court (First Chamber) hereby rules:
A medicinal product, such as Nivalin at issue in the main proceedings, which falls outside the scope of Regulation (EC) No
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation
and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, and the placing
of which on the market in a Member State was not authorised in accordance with the applicable Community law, cannot be considered
to be a reference medicinal product within the meaning of Article 10(2)(a) of Directive 2001/83/EC of the European Parliament
and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, as amended by Directive
2004/27/EC of the European Parliament and of the Council of 31 March 2004.
[Signatures]
*
Language of the case: English.