1. The reference for a preliminary ruling concerns the interpretation of Article 4.8(a)(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 proprietary medicinal products (OJ, English Special Edition 1965-1966, p. 24), 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; ‘Directive 65/65’). Legal background Community legislation
2. Article 3 of Directive 65/65 provides that the issuing of a marketing authorisation (‘MA’) is a necessary condition for a medicinal product to be put on the market of a Member State.
3. Article 4 of that directive provides: ‘In order to obtain an authorisation to place a proprietary 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: … iii) … 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; … a Member State may … extend this period to 10 years by a single Decision covering all the products marketed in its territory where it considers this necessary in the interests of public health … However, where the proprietary medicinal product is intended for a different therapeutic use from that of the other proprietary medicinal products marketed or is to be administered by different routes or in different doses, the results of appropriate pharmacological and toxicological tests and/or of appropriate clinical trials must be provided. b) …’
4. The procedures introduced by Article 4.8(a)(i) to (iii) of Directive 65/65 are commonly referred to as ‘abridged procedures’. The specific procedure for obtaining MAs introduced by the final subparagraph of Article 4.8(a) (‘the proviso’) is known as a ‘hybrid’ abridged procedure. The dispute in the main proceedings and the questions referred
5. SmithKline Beecham plc (‘SmithKline Beecham’) is the holder of an MA for the medicinal product ‘Seroxat’. The active substance of Seroxat is paroxetine hydrochloride hemi-hydrate in dosages of 20 and 30 mg. The first MA for Seroxat was obtained in 1993.
6. In July 1999, the companies Synthon BV and Genthon BV (‘Synthon and Genthon’) submitted largely identical applications for MAs with the competent Danish authority - the Lægemiddelstyrelsen - in respect of Paroxetine ‘Synthon’ and Paroxetine ‘Genthon’ (‘the Synthon/Genthon product’). Their applications were made pursuant to the abridged procedure, citing Seroxat as the reference product.
7. Like Seroxat, the Synthon/Genthon product contains paroxetine, but in the form of a different salt, paroxetine mesylate.
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: … iii) … 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; … a Member State may … extend this period to 10 years by a single Decision covering all the products marketed in its territory where it considers this necessary in the interests of public health … However, where the proprietary medicinal product is intended for a different therapeutic use from that of the other proprietary medicinal products marketed or is to be administered by different routes or in different doses, the results of appropriate pharmacological and toxicological tests and/or of appropriate clinical trials must be provided. b) …’ 4. The procedures introduced by Article 4.8(a)(i) to (iii) of Directive 65/65 are commonly referred to as ‘abridged procedures’. The specific procedure for obtaining MAs introduced by the final subparagraph of Article 4.8(a) (‘the proviso’) is known as a ‘hybrid’ abridged procedure. The dispute in the main proceedings and the questions referred 5. SmithKline Beecham plc (‘SmithKline Beecham’) is the holder of an MA for the medicinal product ‘Seroxat’. The active substance of Seroxat is paroxetine hydrochloride hemi-hydrate in dosages of 20 and 30 mg. The first MA for Seroxat was obtained in 1993. 6. In July 1999, the companies Synthon BV and Genthon BV (‘Synthon and Genthon’) submitted largely identical applications for MAs with the competent Danish authority - the Lægemiddelstyrelsen - in respect of Paroxetine ‘Synthon’ and Paroxetine ‘Genthon’ (‘the Synthon/Genthon product’). Their applications were made pursuant to the abridged procedure, citing Seroxat as the reference product. 7. Like Seroxat, the Synthon/Genthon product contains paroxetine, but in the form of a different salt, paroxetine mesylate. 8. In addition to the documentation which they were required to submit under the abridged procedure, Synthon and Genthon supplied results from selected pharmacological and toxicological tests on animals of the type referred to in the Annex to 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 91/507/EEC of 19 July 1991 (OJ 1991 L 270, p. 32; ‘Directive 75/318‘). The Lægemiddelstyrelsen subsequently requested further information.
9. Using a derogation arising from the fact that use of the Synthon/Genthon product in humans was already documented indirectly by way of bioequivalence to the reference product, Seroxat, tested on healthy volunteers, Synthon and Genthon did not submit results of clinical trials on patients.
10. On the basis of a pre-clinical study of paroxetine salt in relation to the documentation submitted, the Lægemiddelstyrelsen concluded that there were hardly any differences between the two paroxetine salts as far as toxicity was concerned, but that the paroxetine hydrochloride hemi-hydrate contained in Seroxat was slightly more toxic than the paroxetine mesylate appearing in the pre-clinical documentation of Synthon and Genthon. The external experts of the Lægemiddelstyrelsen, who also made an assessment of the documents annexed to the applications of Synthon and Genthon, concluded inter alia that ‘the pharmacological effect and related side effects are related solely to the paroxetine molecule, and the salt is subordinate, assuming the same bioavailability’. No differences in bioavailability were found between the two salts.
11. On the strength of the file thus constituted, the Lægemiddelstyrelsen granted MAs for the Synthon/Genthon product.
12. SmithKline Beecham brought an action before the Østre Landsret challenging the legality of the decision of the Lægemiddelstyrelsen authorising the Synthon/Genthon product.
13. It argues that Seroxat and the Synthon/Genthon product are not essentially similar because they contain different, albeit related, active substances. The fact that further pharmacological and toxicological data were necessary in order to demonstrate essential similarity is sufficient to confirm that the active substances in Seroxat and in the Synthon/Genthon product are different. The submission of further particulars in the form of pharmacological and toxicological tests or clinical trials in the context of an abridged procedure is, the company argues, permitted only pursuant to the proviso, namely where the new product is intended for a different therapeutic indication, or is to be administered by different routes or in different doses.
14. By decision of 14 February 2003, the Østre Landsret decided to stay the proceedings and refer the following questions to the Court: ‘1) Is it compatible with Article 4.8(a)(iii) of Directive 65/65 … for a product to be authorised under the abridged application procedure when a salt of the active substance in the product is changed from the one used in the reference product? 2) Can the abridged application procedure be used when an applicant, on its own initiative or at the request of national health authorities, submits additional documentation in the form of certain pharmacological or toxicological tests or clinical trials with a view to demonstrating that the product is “essentially similar to” the reference product?’ The questions referred Preliminary observations
15. The national court is in doubt as to whether the Synthon/Genthon product is essentially similar to Seroxat, within the meaning of Article 4.8(a)(iii) of Directive 65/65, even though the active substance of the two products is different as regards the salts used.
16. In its judgment in Case C-368/96 Generics (UK) and Others [1998] ECR I-7967, paragraph 36, the Court held that a medicinal product is essentially similar to an original medicinal product, for the purposes of Article 4.8(a)(iii) of Directive 65/65, 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.
17. In the main proceedings, it is undisputed that, in cases where the active substances of two given medicinal products differ as regards the salts used, the applicant for a MA must, as a rule, supply further data in order to demonstrate that the two products do not differ as regards safety and efficacy.
18. SmithKline Beecham and the United Kingdom Government argue that, if only for that reason, two products containing substances which differ as to the salts used are not essentially similar within the meaning of Article 4.8(a)(iii) of Directive 65/65. Two medicinal products are not essentially similar if further data have to be supplied in order to demonstrate that similarity.
19. In relation to the scheme of Directive 65/65, they underline the importance of the distinction between the abridged procedure under Article 4.8(a)(iii) and the hybrid abridged procedure pursuant to the proviso. In their submission, that distinction would be undermined if the definition of essential similarity adopted by the Court in Generics were to be relaxed and the routine submission of additional data were allowed in a wider range of circumstances than those expressly or impliedly included within the proviso.
20. They submit that the Court’s definition of essential similarity in Generics should be interpreted in such a way that, when the identified criteria are met, it can safely be assumed that the two products being compared will have the same safety and efficacy profile. The final condition, namely that the two produc ts should not differ substantially in terms of their safety and efficacy, should be employed only as an additional safeguard against the risk that a change in the excipients used might render the new product less safe or efficacious.
21. Since an applicant normally has to submit additional data in order to demonstrate that, despite the change of salt form, no significant difference arose as to the safety and efficacy of the two products to be compared, SmithKline Beecham and the United Kingdom Government submit that the criterion ‘of having the same qualitative and quantitative composition in terms of active principles’ is no longer an independent criterion.
22. It is that line of argument which has prompted the second question, which it will be appropriate to answer first. The second question
23. In that respect, it should be noted that, in accordance with the wording itself of Article 4.8(a) of Directive 65/65, the applicant is not required to supply the results of pharmacological and toxicological tests or of clinical trials if he can demonstrate that his product is essentially similar to the reference product. Such a demonstration may well necessitate the applicant supplying additional data.
24. There is, moreover, nothing in the proviso to suggest that additional data may be supplied only pursuant to that provision. Data submitted in the context of the proviso and those referred to in Article 4.8(a)(iii) of Directive 65/65 pursue different aims. The former are designed to compensate for a lack of essential similarity, whereas the latter go to prove the existence of that similarity.
25. In those circumstances, the answer to the second question must be that, in support of an application under Article 4.8(a)(iii) of Directive 65/65, an applicant may, either spontaneously or at the request of the competent authority of a Member State, supply additional documentation in the form of certain pharmacological and toxicological tests or clinical trials in order to demonstrate that his product is essentially similar to the reference product. The first question
26. Concerning the national court’s first question, SmithKline Beecham and the United Kingdom Government argue that, on account of the difference in the active substance used, Seroxat and the Synthon/Genthon product are not essentially similar. They refer to the definition of the concept of essential similarity arising from the Generics judgment, whereby the medicinal product in question is essentially similar if, inter alia, it satisfies the criterion of having the same qualitative and quantitative composition in terms of active principles. In this case, they argue, the difference in the salts used prevents the corresponding substances from being identical.
27. SmithKline Beecham and the United Kingdom Government argue that merely substituting one salt for another in a medicinal product may affect its therapeutic efficacy, by increasing or reducing the absorption of that product and its bioavailability, or may affect its toxic potential or stability and entail negative effects.
28. According to Synthon and Genthon, the Danish and Netherlands Governments and the Commission, the criterion defined in Generics does not mean that there must be an exact molecular match between the active ingredients. They submit that the decision should be based on an assessment of the therapeutic action of the two medicinal products to be compared.
29. Synthon and Genthon and the Danish Government point out that the negative part of the salt, namely the part that is different in the medicinal products concerned, constitutes only an inert element which allows the product to be manufactured in the form of tablets. They maintain that, when such a tablet is swallowed, the two parts of the salt which enter into the composition of that tablet separate and only the positive part of the salt is absorbed, while the other part is eliminated by the body.
30. Similarly, where the active substance of the medicinal products to be compared is, as in the case at issue in the main proceedings, combined with different salts, the Commission and the Netherlands Government make a distinction between the part of that salt which is therapeutically active and the negative part, which they term the inert element.
31. It should be noted in that respect that, in its judgment in Generics , the Court did not define the term ‘active principle’.
32. As is apparent from the observations submitted to the Court, that term is used to designate both the therapeutically active part of an active substance and the active substance itself.
33. It does not follow from the criterion of essential similarity as laid down by the Court in Generics that there must be an exact molecular match between the active ingredients.
34. Neither the wording of Article 4.8(a)(iii) of Directive 65/65, which merely requires essential similarity between the two medicinal products, or the definition of that term given by the Court in Generics exclude the possibility that two products which are not identical, in so far as their active substance contains different salts, might be essentially similar products for the purposes of that provision.
35. Moreover, the parties in the main proceedings, the Governments which have submitted observations and the Commission seem to agree that, where an examination is made as to whether two products are essentially similar, it is more realistic to base one’s enquiry on therapeutic action than on the precise molecular structure of the active ingredients.
36. Even if, as the United Kingdom Government in particular argues, there may in exceptional cases be a risk that replacing one form of salt with another entails a change affecting the safety or efficacy of the product, even where the therapeutically active part remains the same, that risk is not in itself sufficient for a finding that the difference in the salts used in the active substance implies that the products are not essentially similar for the purposes of Article 4.8(a)(iii) of Directive 65/65.
37. That risk is no different from that which might result from a change affecting any other inert element of a medicinal product.
38. It is precisely in order to avoid such a risk that, in accordance with the definition arising from the Generics judgment, medicinal products are not regarded as essentially similar if it appears, taking account of scientific knowledge, that the medicinal product for which a MA is sought shows significant differences from the original product as regards safety or efficacy.
39. A difference such as that at issue in this case cannot normally prevent two medicinal products from being regarded as essentially similar. That cannot be the case if, for reasons specifically identified, that difference must be regarded as significant as regards the safety or efficacy of the product for which the MA is sought.
40. As for the argument of the United Kingdom Government that the definition of essential similarity must be applied strictly in order to maintain a fair balance between the interests of innovator companies and those of the manufacturers of generic products, suffice it to say that the former are protected by the 6 or 10 year period of data exclusivity provided for under Article 4.8(a)(iii) of Directive 65/65 and that the requirement of essential similarity is designed primarily to safeguard public health.
41. Moreover, the interpretation that two medicinal products may be essentially similar for the purposes of Article 4.8(a)(iii) of Directive 65/65, even if their active substances are combined with different salts, is the interpretation which best corresponds to the specific objective of the abridged procedure, which is to allow economy of time and necessary costs in collating the results of pharmacological and toxicological tests and clinical trials, and to avoid the repetition of tests on humans or animals.
42. Furthermore, an interpretation whereby two different salts containing the same therapeutically active part may be essentially similar for the purposes of Article 4.8(a)(iii) of Directive 65/65 is the interpretation adopted in the guidelines published by the Commission in ‘The rules governing medicinal products in the European Community, Volume II: Notice to applicants for marketing authorisations for medicinal products for human use in the Member States of the European Community’ in its version of 1998, which was in force when Synthon and Genthon submitted applications for MA for their products.
43. Finally, and for the same reasons as those set out by the Advocate General in his Opinion, the Court must reject the arguments of SmithKline Beecham and the United Kingdom Government based, respectively, on: - the definition of ‘qualitative composition’ of a medicinal product given in the Annex to Directive 75/318, implying that the active ingredient should be understood, in the case of salts, to include both the therapeutic moiety and the appended portion of the molecule, and should be identified as such (see point 80 of the Opinion); - the reference made to Commission Regulation (EC) No 541/95 of 10 March 1995 concerning the examination of variations to the terms of a marketing authorisation granted by a competent authority of a Member State (OJ 1995 L 55, p. 7), Annex II of which requires that a new MA be applied for in the event of ‘changes to the active substance(s)’, which, according to that Annex, includes ‘replacement of the active substance(s) by a different salt … (with the same therapeutic moiety)’ (paragraph 82); - definitions contained in Commission Regulation (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 definitions of the concepts ‘similar medicinal product’ and ‘clinical superiority’ (OJ 2000 L 103, p. 5) (paragraphs 85 to 89).
44. In the light of the above considerations as a whole, the answer to the first question must be that Article 4.8(a)(iii) of Directive 65/65 must be interpreted as not preventing an application for a MA in respect of a medicinal product from being handled under the abridged procedure under that provision where that product contains the same therapeutic moiety as the reference product but combined with another salt.