CELEX: 62003CJ0036
Medicinal products
Marketing authorisation
Procedures for essentially similar products

The question referred for a preliminary ruling concerns the interpretation of Article 10(1)(a)(iii) 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).
The question was raised in proceedings between Approved Prescription Services Ltd (‘APS’) and the Licensing Authority, acting
by the Medicines and Healthcare products Regulatory Agency (‘MHRA’), concerning an application for marketing authorisation
for a medicinal product.
Legal background
Under Article 6(1) of Directive 2001/83, no medicinal product may be placed on the market of a Member State unless a marketing
authorisation has been issued.
Article 8(3)(i) of Directive 2001/83 provides:
‘The application [for the grant of a marketing authorisation] shall be accompanied by the following particulars and documents,
submitted in accordance with Annex I:
…
(i) Results of:
–
physico-chemical, biological or microbiological tests,
–
toxicological and pharmacological tests,
–
clinical trials.’
In the version in force at the time of the facts of the main case, Article 10(1)(a) of Directive 2001/83 provided:
‘In derogation of Article 8(3)(i), and without prejudice to the law relating to the protection of industrial and commercial
property:
(a)

The applicant shall not be required to provide the results of toxicological and pharmacological tests or the results of clinical
trials if he can demonstrate:
…
(iii)

… that the medicinal product is essentially similar to a medicinal product which has been authorised within the Community,
in accordance with Community provisions in force, for not less than six years and is marketed in the Member State for which
the application is made. … a Member State may … extend this period to 10 years by a single Decision covering all the medicinal
products marketed on its territory where it considers this necessary in the interest of public health. …

However, where the medicinal product is intended for a different therapeutic use from that of the other medicinal products
marketed or is to be administered by different routes or in different doses, the results of appropriate toxicological and
pharmacological tests and/or of appropriate clinical trials must be provided.’
The procedures laid down in Article 10(1)(a)(i) to (iii) of Directive 2001/83 are commonly known as ‘abridged procedures’.
The special procedure for obtaining marketing authorisation provided for in the final paragraph of Article 10(1)(a) (‘the
proviso’) is known as a ‘hybrid’ abridged procedure.
The United Kingdom of Great Britain and Northern Ireland has exercised the option granted to the Member States by Article
10(1)(a)(iii) of Directive 2001/83 and has extended the period referred to therein to ten years.
Facts and the question referred for a preliminary ruling
The main case concerns three medicinal products, each of them containing the active ingredient Fluoxetine.
Two of those medicinal products are produced by Eli Lilly & Co. Ltd (‘Eli Lilly’). The first, Prozac capsules, was the first
product containing Fluoxetine as an active ingredient to be granted marketing authorisation in the Community. It was authorised
in the United Kingdom on 25 November 1988. The second is Prozac liquid, which was first authorised in the Community on 14
October 1992 in Denmark. Marketing authorisation for Prozac liquid was granted in the United Kingdom on 28 October 1992 following
an application made by Eli Lilly under the hybrid abridged procedure. The reference product to which Eli Lilly’s application
referred was Prozac capsules. When making its application, Eli Lilly conceded that Prozac liquid was not essentially similar
to Prozac capsules, on account of its different pharmaceutical form, and submitted additional data intended to show that they
were bioequivalent.
The third medicinal product in question in the main case, called Fluoxetine liquid 20 mg/5ml, is produced by APS.
In October 1999, APS applied to the MHRA for marketing authorisation for that medicinal product.
APS sought to rely on the abridged procedure under Article 10(1)(a)(iii) of Directive 2001/83 on the ground that its product
was essentially similar to Prozac liquid. It also stated that the date of first marketing authorisation for its reference
medicinal product was 25 November 1988, which is the date on which marketing authorisation for Prozac capsules was granted
in the United Kingdom.
The MHRA took the view that APS could not use Prozac liquid as a reference product for the purposes of Article 10(1)(a)(iii)
of Directive 2001/83 because, at the time when APS made its application, that medicinal product had been authorised in the
Community for less than ten years.
APS was therefore asked to amend its application so as, this time, to cite as the reference medicinal product Prozac capsules,
which had been authorised for more than ten years. According to the MHRA, since that product was not essentially similar to
Fluoxetine liquid, APS ought to have applied under the hybrid abridged procedure and supplied additional data in the form
of a bioequivalence study comparing the two medicinal products.
APS brought an application for judicial review of the MHRA’s decision before the High Court, in which it claimed that it was
entitled to rely on the data supplied in respect of Prozac liquid.
It was against this background that the High Court decided to stay the proceedings and to refer the following question to
the Court for a preliminary ruling:
‘Can an application for a marketing authorisation for a medicinal Product C validly be made under the first paragraph of Article
10(1)(a)(iii) of Directive 2001/83, where the application seeks to demonstrate that Product C is essentially similar to another
product, Product B, in circumstances where:
–

Product B is related to an original medicinal Product A, in that Product B has been authorised as a “line extension” of Product
A, but has a different pharmaceutical form from Product A or is otherwise not “essentially similar” to Product A within the
meaning of Article 10(1)(a)(iii); and
–

Product A has been authorised for marketing in the Community for more than the six/ten year period stipulated in Article 10(1)(a)(iii);
and
–

Product B has been authorised for marketing for less than the six/ten year period stipulated in Article 10(1)(a)(iii)?’
The question referred for a preliminary ruling
A medicinal product is essentially similar, within the meaning of Article 10(1)(a)(iii) of Directive 2001/83, to an original
medicinal product where it satisfies the criteria of having the same qualitative and quantitative composition in terms of
active principles, of having the same pharmaceutical form and of being bioequivalent, unless it is apparent in the light of
scientific knowledge that it differs significantly from the original product as regards safety or efficacy (Case C‑368/96
Generics (UK) and Others
[1998] ECR I‑7967, paragraph 36, concerning an equivalent provision in 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, p. 20).
Under Article 10(1)(a)(iii) of Directive 2001/83, where it has been established that a medicinal product is essentially similar
to a product which has been authorised within the Community for at least six or ten years and is marketed in the Member State
for which the application is made, the applicant is not required to provide the results of toxicological and pharmacological
tests or of clinical trials. According to the final paragraph of that provision, ‘where the medicinal product is intended
for a different therapeutic use from that of the other medicinal products marketed or is to be administered by different routes
or in different doses, the results of appropriate toxicological and pharmacological tests and/or of appropriate clinical trials
must be provided’.
At the hearing, APS, the United Kingdom, Danish, French and Netherlands Governments and the Commission all referred to the
judgment of 29 April 2004 in Case C‑106/01
Novartis Pharmaceuticals
[2004] ECR I‑0000, which was delivered after they had submitted their written observations but before the hearing. They take
the view that it is a necessary implication of the reasoning followed by the Court in that judgment that, in circumstances
such as those of the main case, it must be permissible to apply for marketing authorisation for Product C under the abridged
procedure even where Product B has been authorised in the Community for less than ten years and even though Products A and
B are not essentially similar within the meaning of the Directive because they have a different pharmaceutical form.
Eli Lilly, which took the contrary view in its written observations, was not present at the hearing.
The Court finds that the position taken by the parties which presented oral argument, namely that the reasoning followed by
the Court in
Novartis Pharmaceuticals
, cited above, can be applied to the main case, is well founded.
In its judgment in that case, the Court interpreted Article 4.8(a) of Directive 65/65. However, the wording of Article 10(1)(a)
of Directive 2001/83 is, essentially, identical to that of Article 4.8(a).
The circumstances of the case with which the judgment in
Novartis
Pharmaceuticals
was concerned were as follows: marketing authorisation had been issued in the United Kingdom for the medicinal Product A
more than ten years, and for Product B less than ten years, before the date of the application made for medicinal Product
C. The marketing authorisation for Product B had been granted under the hybrid abridged procedure. Products A, B and C were
not essentially similar within the meaning of Article 4.8(a) of Directive 65/65 because their bioavailability differed.
Referring, in particular, to the proviso, the Court held in, paragraphs 56 to 67 of that judgment, that the applicant for
marketing authorisation for Product C may refer to the pharmacological, toxicological and clinical documentation relating
to a Product B resulting from the development of the reference Product A, even if Products A and B are not essentially similar
on account of their different bioavailability.
The Court held that, if an applicant is entitled under the proviso to refer to the data relating to a variant B which differs
from the reference medicinal product in the route of its administration or dose, since the differences in those two factors
generally imply that products A and B are not bioequivalent, it must,
a fortiori
, likewise be entitled to do so where the two products are distinguishable only by their different bioavailability, even though
the route of administration and dose remain unchanged (see
Novartis Pharmaceuticals
, paragraph 66).
The same reasoning may be followed where the original medicinal product and the variant differ only in that they have a different
pharmaceutical form. Since, as all the parties present at the hearing observed, a new route of administration generally entails
a change in pharmaceutical form, the situation to be examined in the main case is analogous to that in
Novartis Pharmaceuticals
.
Moreover, as the Advocate General pointed out in paragraphs 14 to 18 and 69 to 73 of his Opinion, this conclusion is supported
by the Notice to applicants for marketing authorisations for medicinal products for human use in the Member States of the
European Community, which was published by the Commission in 2001.
Whilst the United Kingdom Government concurs with the reasoning followed in paragraph 26 of the present judgment, it argues
that it also follows from the
Novartis Pharmaceuticals
judgment that, in circumstances such as those of the main case, an applicant for marketing authorisation may refer to the
data relating to Product B only if its application is made pursuant to the proviso.
It need be stated only that, although the reasoning followed in
Novartis Pharmaceuticals
makes reference to the provision laying down the proviso, it by no means follows that the applicant for marketing authorisation
for product C must rely on that provision when making its application.
In the light of the foregoing, the answer to the question referred must be that an application for marketing authorisation
for a Product C may be made under Article 10(1)(a)(iii) of Directive 2001/83 where the application seeks to demonstrate that
Product C is essentially similar to a Product B, in circumstances where:
–
Product B is a new pharmaceutical form of Product A, and
–
Product A, but not Product B, has been authorised for marketing in the Community for at least the six or ten year period stipulated
therein.
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 (Second Chamber) rules as follows:
An application for marketing authorisation for a Product C may be made under Article 10(1)(a)(iii) 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 where the application seeks to demonstrate that Product C is essentially similar to a Product B, in circumstances
where:
–
Product B is a new pharmaceutical form of Product A, and
–
Product A, but not Product B, has been authorised for marketing in the Community for at least the six or ten year period stipulated
therein.
Signatures.
–
Language of the case: English.