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You are here: BAILII >> Databases >> Court of Justice of the European Communities (including Court of First Instance Decisions) >> Novartis Pharmaceuticals (Approximation of laws) [2004] EUECJ C-106/01 (29 April 2004) URL: https://www.bailii.org/eu/cases/EUECJ/2004/C10601.html Cite as: Case C-106/01, [2004] 2 CMLR 26, [2004] EUECJ C-106/01, [2004] EUECJ C-106/1, [2004] ECR I-4403 |
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JUDGMENT OF THE COURT (Sixth Chamber)
29 April 2004
(1)
(Medicinal products - Marketing authorisation - Procedure relating to essentially similar products)
In Case C-106/01, REFERENCE to the Court under Article 234 EC by the Court of Appeal (Civil Division) (England and Wales) for a preliminary ruling in the proceedings pending before that court between The Queen on the application of Novartis Pharmaceuticals UK Ltdand
The Licensing Authority established by the Medicines Act 1968 (acting by the Medicines Control Agency), and SangStat UK Ltd, and Imtix-SangStat UK Ltd, on the interpretation of Article 4.8(a) of 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), as amended by Council Directives 87/21/EEC of 22 December 1986 (OJ 1987 L 15, p. 36), 89/341/EEC of 3 May 1989 (OJ 1989 L 142, p. 11) and 93/39/EEC of 14 June 1993 (OJ 1993 L 214, p. 22),THE COURT (Sixth Chamber),
after considering the written observations submitted on behalf of:
- Novartis Pharmaceuticals UK Ltd, by I. Dodds-Smith and R. Hughes, Solicitors, D. Anderson QC, and J. Stratford, Barrister, - SangStat UK Ltd and Imtix-SangStat UK Ltd, by T. Cook and J. Mutimear, Solicitors, - the United Kingdom Government, by J.E. Collins, acting as Agent, P. Sales, Barrister and R. Singh QC, - the Danish Government, by J. Molde, acting as Agent, - the French Government, by G. de Bergues and R. Loosli-Surrans, acting as Agents, - the Portuguese Government, by L.I. Fernandes, acting as Agent, - the Commission of the European Communities, by H.C. Støvlbæk and R. Wainwright, acting as Agents,having regard to the Report for the Hearing,
after hearing the oral observations of Novartis Pharmaceuticals UK Ltd, SangStat UK Ltd and Imtix-SangStat UK Ltd, the United Kingdom Government, represented by K. Manji, acting as Agent, and P. Sales, the Danish Government, the Netherlands Government, represented by J.G.M. van Bakel, acting as Agent, and the Commission, represented by H.C. Støvlbæk and M. Shotter, acting as Agent, at the hearing on 7 November 2002,
after hearing the Opinion of the Advocate General at the sitting on 23 January 2003,
gives the following
'In order to obtain an authorisation to place a medicinal product on the market as provided for in Article 3, the person responsible for placing that product on the market shall make application to the competent authority of the Member State concerned. ... The application shall be accompanied by the following particulars and documents: ... 8. Results of: - physico-chemical, biological or microbiological tests, - pharmacological and toxicological tests, - clinical trials. However, 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 pharmacological and toxicological tests or the results of clinical trials if he can demonstrate: (i) either that the medicinal product is essentially similar to a product authorised in the country concerned by the application and that the person responsible for the marketing of the original medicinal product has consented to the pharmacological, toxicological or clinical references contained in the file on the original medicinal product being used for the purpose of examining the application in question;
...
or that the medicinal product is essentially similar to a 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; this period shall be extended to 10 years in the case of high-technology medicinal products within the meaning of Part A in the Annex to Directive 87/22/EEC or of a medicinal product within the meaning of Part B in the Annex to that directive for which the procedure laid down in Article 2 thereof has been followed; furthermore, a Member State may also extend this period to 10 years by a single decision covering all the products marketed on its territory where it considers this necessary in the interest of public health. Member States are at liberty not to apply the abovementioned six-year period beyond the date of expiry of a patent protecting the original product. 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 pharmacological and toxicological texts and/or of appropriate clinical trials must be provided. (b) ...'
'The authorisation provided for in Article 3 shall be refused if, after verification of the particulars and documents listed in Article 4, it proves that the medicinal product is harmful in the normal conditions of use, or that its therapeutic efficacy is lacking or is insufficiently substantiated by the applicant, or that its qualitative and quantitative composition is not as declared. Authorisation shall likewise be refused if the particulars and documents submitted in support of the application do not comply with Article 4.'
(a) cross-referred unlawfully to the Neoral file (the cross-reference issue); (b) erred in finding that SangCya was essentially similar to Sandimmun, thereby exempting SangStat from the requirement to demonstrate that its product was safe notwithstanding its lack of bioequivalence with Sandimmun (the essential similarity issue); (c) infringed the principle of non-discrimination between Novartis and SangStat in terms of the authorisation procedure (the non-discrimination issue).
(a) it was entitled to cross-refer to all information in its possession in assessing whether a product for which marketing authorisation was sought was safe; (b) questions of essential similarity were inherently questions of fact, degree and expert opinion for the competent national authorities, which enjoy a margin of discretion in deciding issues such as whether two products have the same pharmaceutical form. In any event, bioequivalence is not always required in order to demonstrate essential similarity; (c) there was no infringement of the principle of non-discrimination since Novartis and SangStat were not in the same position and, in any event, there was an objective and reasonable basis for distinguishing them.
'1. In considering a marketing authorisation for a new product (C) under Article 4.8(a)(iii) of Directive 65/65, referencing a product (A) authorised more than 6/10 years ago, is a national competent authority ever entitled to cross-refer, without consent, to data submitted in support of a product (B) which was authorised within the last 6/10 years? 2. If so, may such cross-reference be made in circumstances where: (a) product B was authorised under the Article 4.8(a) hybrid abridged procedure, referencing product A; and (b) the data to which reference is made consists of clinical trials which the national competent authority indicated would be necessary if the marketing authorisation was to be granted and which were submitted in order to demonstrate that product B, though suprabioavailable to product A when administered in the same dose, is safe? 3. (a) Does the final subparagraph of Article 4.8(a) of Directive 65/65 ("the proviso") apply only to applications made under Article 4.8(a)(iii) or to applications made under Article 4.8(a)(i) also? (b) Is essential similarity a prerequisite for the use of the proviso? 4. Can products ever be essentially similar for the purposes of Article 4.8(a)(i) and (iii) of Directive 65/65 when they are not bioequivalent, and if so in what circumstances? 5. What is the meaning of the term pharmaceutical form, as used by the Court in its judgment in Case C-368/96 Generics? In particular, do two products have the same pharmaceutical form when they are administered to the patient in the form of a solution diluted to a macroemulsion, microemulsion and nanodispersion respectively? 6. Is it consistent with the general principle of non-discrimination for a national competent authority, faced with hybrid applications for marketing authorisations under Article 4.8(a) of Directive 65/65 referencing product A for two products, neither of which is bioequivalent to product A: (i) to indicate that it is necessary for a marketing authorisation to be granted for product B to be supported by full clinical data of the type required by Part 4(F) of the Annex to Directive 75/318/EEC; but (ii) having considered the data filed in support of product B, to grant a marketing authorisation for product C if that application is supported by trials not meeting the requirements of Part 4(F) of the Annex to Directive 75/318/EEC?'
- Neoral and SangCya are not bioequivalent since their bioavailability differs; - Neoral had been authorised for less than 10 years; - Neoral is a development of Sandimmun since Novartis obtained marketing authorisation for Neoral under the hybrid abridged procedure.
- the procedure established by that provision enables a second applicant for marketing authorisation for a given product to save the time and expense necessary in order to gather the pharmacological, toxicological and clinical data. In accordance with the fourth recital in the preamble to Directive 87/21, it also avoids, on public policy grounds, the repetition of tests on humans or animals where not absolutely necessary (Generics, paragraph 4); - under the abridged procedure, the obligation to carry out pharmacological, toxicological and clinical tests is replaced by an obligation to show that the medicinal product is so similar to a product which has been authorised for not less than six or 10 years in the Community and is marketed in the Member State for which the application is made that it does not differ significantly from that product as regards safety and efficacy, and that it is therefore essentially similar to the product already authorised (Generics, paragraph 24); - a medicinal product is essentially similar, within the meaning of Article 4.8(a)(iii) of Directive 65/65, as amended, 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 (Generics, paragraph 36); - a medicinal product that is essentially similar to a product which has been authorised for not less than six or 10 years and is marketed in the Member State for which the application is made may be authorised, under the abridged procedure, for all therapeutic indications already authorised for that product, even if those indications have been authorised for less than six or 10 years (Generics, paragraph 53). The Court stated in this connection that it is, where appropriate, for the Community legislature to adopt measures to reinforce the rules for the protection of innovating undertakings in the harmonised area with which the case is concerned (Generics, paragraph 52).
The fifth question
The second part of the third question
On those grounds,
THE COURT (Sixth Chamber)
in answer to the questions referred to it by the Court of Appeal (Civil Division) (England and Wales) by order of 22 February 2001, hereby rules: 1) Products cannot be regarded as essentially similar for the purposes of the application of Article 4.8(a)(i) or (iii) of 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, as amended by Council Directives 87/21/EEC of 22 December 1986, 89/341/EEC of 3 May 1989, and 93/39/EEC of 14 June 1993, where they are not bioequivalent. 2) For the purposes of the procedure laid down by Article 4.8(a)(i) and (iii) of Directive 65/65, as amended, in determining the pharmaceutical form of a medicinal product, account must be taken of the form in which it is presented and the form in which it is administered, including the physical form. In that context, medicinal products such as those at issue in the main proceedings, which are presented in the form of a solution to be mixed in a drink for administration to the patient and which, after mixing, form, respectively, a macroemulsion, a microemulsion and a nanodispersion, are to be treated as having the same pharmaceutical form, provided that the differences in the form of administration are not significant in scientific terms. 3) The proviso, that is, the hybrid abridged procedure laid down by the final subparagraph of Article 4.8(a) of Directive 65/65, as amended, applies to applications for marketing authorisation based on Article 4.8(a)(i) or (iii). An application for marketing authorisation for a medicinal product may be made under the proviso, that is, by the abridged hybrid procedure provided for in the final subparagraph of Article 4.8(a) of Directive 65/65, as amended, with reference to an authorised medicinal product provided that the medicinal product in respect of which marketing authorisation is sought is essentially similar to the authorised medicinal product, unless one or more of the differences set out in the proviso apply, as the case may be. 4) In considering an application for marketing authorisation for a new product C under Article 4.8(a)(iii) of Directive 65/65, as amended, with reference to a product A authorised for more than six or 10 years, the competent authority of a Member State is entitled, with a view to granting marketing authorisation, to refer without the consent of the person responsible for marketing to data submitted in support of a product B which was authorised within the previous six or 10 years under the hybrid abridged procedure laid down by Article 4.8(a) of Directive 65/65, as amended, with reference to product A, where those data consist of clinical trials provided in order to demonstrate that product B, though suprabioavailable to product A when administered in the same dose, is safe. 5) In considering two hybrid applications for marketing authorisation for products B and C brought under the final subparagraph of Article 4.8(a) of Directive 65/65, as amended, and referring to product A, the competent authority of a Member State does not infringe the principle of non-discrimination where, as a precondition for the grant of marketing authorisation, it requires full clinical data on the bioavailability of product B, but, having examined the data filed in support of product B, does not require the same data for product C.
Skouris |
Gulmann |
Cunha Rodrigues |
Puissochet |
Schintgen |
|
R. Grass |
V. Skouris |
Registrar |
President |
1 - Language of the case: English.