C-368/96

3 2. Those questions relate to use of the sim­ 3. Medicinal products intended for human plified procedure for obtaining a marketing use have considerable repercussions on public authorisation for generic medicinal products health and it is therefore necessary for their by reference to documentation which the marketing to be strictly controlled by the innovating pharmaceutical undertaking pro­ authorities. In order progressively to reduce duced in order to obtain authorisation for the obstacles to the free movement of medicinal original medicinal product. The specific issue products in the Community resulting from here is whether the authorisation for the gen­ divergences between national systems of con­ eral medicinal product should extend to all trol, the Community institutions have adopted the indications and dosage schedules autho­ numerous rules to harmonise controls on the rised for the original medicinal product up to marketing of medicinal products. that time or whether, on the contrary, the protection period of 10 years for the original 3 — I shall treat the terms 'medicinal product' and 'proprietary medicinal product' as equivalent, even though the scope of the first term is wider than that of the second. The first covers not only medicinal products produced industrially and, in * Original language: Spanish. particular, generic medicinal products (that is to say, medicinal 1 — Directive 65/65/EEC of the Council of 26 January 1965 on products similar to existing products not already protected by the approximation of provisions laid down by law, regula­ patents) but also proprietary medicinal products (that is to tion or administrative action relating to proprietary medicinal say, medicinal products prepared and marketed under a spe­ products (OJ English Special Edition 1965-1966, p. 20). cial name and in special packaging). Since the adoption of 2 — Council Directive 87/21/EEC of 22 December 1986 amending Council Directive 89/341/EEC of 3 May 1989 amending Council Directive 65/65/EEC of 26 January 1965 on the Directives 65/65/EEC, 75/318/EEC and 75/319/EEC (OJ approximation of provisions laid down by law, regulation or 1989 L 142, p. 11) the term medicinal product has been sub­ administrative action relating to proprietary medicinal prod­ stituted for proprietary medicinal product in all Community ucts (OJ 1987 L 15, p. 36). legislation concerning medicinal products for human use.

The scope of Community authorisations is limited since they are compulsory for tech­ 5 — Mutual recognition of national marketing authorisations has nologically advanced medicinal products and been facilitated by Council Directive 93/39/EEC of 14 June optional for medicinal products which con­ 1993 amending Directives 65/65/EEC, 75/318/EEC and 75/319/EEC in respect of medicinal products (OJ 1993 tain new active principles. L 214, p. 22). 6 — Council Directive 75/318/EEC of 20 May 1975 on the approxi- mation 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 4 — Council Regulation (EEC) No 2309/93 of 22 July 1993 laying (OJ 1975 L 147, p. 1). down Community procedures for the authorisation and super­ 7 — Second Council Directive 75/319/EEC of 20 May 1975 on vision of medicinal products for human and veterinary use the approximation of the provisions laid down by law, regula­ and establishing a European Agency for the Evaluation of tion or administrative action relating to proprietary medicinal Medicinal Products (OJ 1993 L 214, p. 1). products (OJ 1975 L 147, p. 13).

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kinds of procedure: a normal procedure and sible for placing that product on the market a simplified procedure. Under the normal shall make application to the competent procedure, in order to obtain the marketing authority of the Member State concerned. authorisation the applicant must submit the results of a series of pharmacological and toxicological tests and clinical trials, whereas that requirement will not apply, subject to certain conditions, if the matter is processed under the simplified procedure. The latter procedure enables a second applicant to avoid the investment of time and money involved The application shall be accompanied by the in compiling detailed clinical and pre-clinical following particulars and documents: data.

However, and without prejudice to the law within the Community, in accordance relating to the protection of industrial and with Community provisions in force, commercial property: for not less than six years and is mar­ keted 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 (a) The applicant shall not be required to products within the meaning of Part provide the results of pharmacological A in the Annex to Directive and toxicological tests or the results of 87/22/EEC or of a medicinal product clinical trials if he can demonstrate: 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; further­ more, a Member State may also extend (i) either that the proprietary medicinal this period to 10 years by a single product is essentially similar to a decision covering all the products mar­ product authorised in the country keted on its territory where it con­ concerned by the application and that siders this necessary in the interest of the person responsible for the mar­ public health. Member States are at keting of the original proprietary liberty not to apply the abovemen- medicinal product has consented to tioned six-year period beyond the date the pharmacological, toxicological or of expiry of a patent protecting the clinical references contained in the file original product. on the original proprietary medicinal product being used for the purpose of examining the application in question;

from that date, pharmaceutical undertakings 8. In order to protect the industrial and com­ may use the simplified procedure to obtain an mercial property of innovating firms, point authorisation enabling them to market a 8(a)(iii) of the second paragraph of Article 4 medicinal product in the three cases contem­ of Directive 65/65 does not allow recourse to plated in point 8(a) of the second paragraph the simplified procedure and consequent use of Article 4. In the first case, consent must be of the documentation produced by the inno­ procured from the innovating firm holding vating undertaking for a period of 6 or 10 the authorisation for the original medicinal years, as decided by each Member State. The product, which the undertaking producing United Kingdom imposed a period of 10 years the essentially similar medicinal product will as from the issue of the first marketing autho­ have much difficulty in obtaining. In the risation for the medicinal product in question second case, a marketing authorisation may in a Member State of the Community. be obtained on the basis of detailed references to published scientific literature. That possi­ bility was improperly used by the national 8 authorities and Directive 87/21 seeks to rees­ tablish its exceptional nature. Background to the dispute

13. Captopril is a medicinal product devel­ oped as a result of research carried out in the 1970s by Bristol-Myers Squibb (hereinafter 'BMS'), a major research-based pharmaceu­ 11. The applicants in the three cases are phar­ tical manufacturer. It is a compound in the maceutical undertakings specialising in the group of medicinal products called angio­ sale of generic medicinal products or pharma­ tensin converting enzyme inhibitors (ACE ceutical companies oriented towards the sale inhibitors). By a variety of effects (principally of non-generic proprietary medicinal prod­ vasodilation) such compounds have a benefi­ ucts protected by a trade mark, which are cial effect on, inter alia, the cardiovascular developed following very considerable invest­ system. Captopril was the first of such class ment in research. of compounds to be presented as a medicinal product and to receive a marketing authorisa­ tion within the Community.

In response, the MCA informed Generics that it could not give a decision on its application without first analysing the provision relied 15. France was the first Member State to upon and determining its proper interpreta­ grant authorisation for the post-myocardial tion. Generics commenced proceedings for infarction indication, on 1 June 1993. The judicial review, which were compromised on United Kingdom was the first Member State 18 July 1995 on the basis of an agreement to grant authorisation for the diabetic neph­ between the parties, without prejudice to ropathy indication, on 5 May 1994. Substan­ Generics's right to seek further judicial review. tial clinical research involving thousands of The MCA agreed to grant Generics marketing patients was conducted or sponsored by BMS authorisation for Captopril tablets of 12.5 mg, to support each of the post-myocardial inf­ 25 mg and 50 mg for indications which had arction and diabetic nephropathy indications. been approved in the territory of the Com­ In both cases the costs of developing such munity for 10 years. However, it declined to research data and obtaining the authorisations grant authorisations for all the other indica­ exceeded several tens of millions of US dol­ tions for Captopril which had not been approved in the territory of the Community lars. All the other variations referred to above for 10 y ears, namely treatment following myo­ have been the subject of authorisation in other cardial infarction and diabetic nephropathy. Member States for at least 10 years. Only the last two changes of indication and the status of the data underlying them arc at issue in the Captopril proceedings.

18. On 23 October 1995 Generics received a 11 letter from the MCA dated 20 October 1995 which explained the MCA's interpreta­ tion of point 8(a)(iii) of the second paragraph of Article 4 of Directive 65/65. The Aciclovir proceedings

19. Subsequently, the MCA informed Generics that some of the Captopril indica­ tions added over the previous 10 years required 20. Wellcome Foundation Limited (hereinaf­ 13 a new authorisation under Annex II to Regu­ ter 'Wellcome') holds the main authorisa­ lation (EC) No 541/95, 12 and therefore tions for marketing in the United Kingdom remained subject to protection. That was the of the anti-viral product Aciclovir, also mar­ case with regard to the additional indication keted under the brand name 'Zovirax'. Those for 'diabetic nephropathy'. However, the authorisations were granted to Wellcome by MCA accepted that Generics could rely upon the MCA between 1981 and 1994.

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research expenditure amounted to several mil­ Over that period, Wellcome extended consid­ lion pounds per annum; from UKL 4 million erably the indications and dosages for Aci­ in 1982/1983 to UKL 8 million in 1991/1992. clovir.

14 — The progressive extension of the authorised therapeutic indications and dosages may be summarised in two tables, one for aciclovir tablets and the other for aciclovir intravenous infusion.

Aciclovir Tablet Authorisation

Date of UK Date of first EC Country of first UK Indication/Nature of authorisation authorisation EC authorisation Product Variation (+) or variation or variation or variation

26.07.94 06.11.91 Spain Zovirax Tablets + Treatment oí varicela (Chickenpox) infections 800 mg

Aciclovir Intravenous Infusion Authorisation

06.04.82 06.04.82 UK Zovirax I. V. Treatment of infections caused by Herpes simplex 250 mg virus in immunocompromised patients, by the intravenous route.

09.11.83 09.11.83 UK Zovirax I. V. + Profylaxis of Herpes simplex infections in 250 mg severely immunocompromised patients + Treatment of severe initial Varicella zoster (shin­ gles) infections in patients with normal immune responses; primary and recurrent Varicella zoster in immunocompromised patients

09.04.86 09.04.86 UK Zovirax I. V. + Treatment of Herpes encephalitis 250 mg

24.11.89 24.11.89 UK Zovirax I. V. + 500 mg Presentation 250 mg Zovirax I. V. 500 mg

23. Wellcome became aware of the details of five marketing authorisations granted by the MCA to A/S Gea Farmaceutisk Fabrik (here­ inafter 'Gea') for different indications and 25. Between 1981 and 1995 the MCA granted dosage forms of Aciclovir tablets and intra­ to Glaxo Operations UK Limited, Glaxo venous infusion. Those authorisations had Wellcome UK Limited (formerly Glaxo Phar­ been published in The London Gazette on 31 maceuticals UK Limited), Glaxo Research May 1996 and were dated 29 February 1996. and Development Limited (formerly Glaxo They had been granted for Aciclovir tablets Group Research Limited) and Glaxo Group of 200 mg, 400 mg and 800 mg and for intra­ Limited (hereinafter 'Glaxo'), which are all venous infusions of 250 mg and 500 mg, and subsidiaries of Glaxo Wellcome pic, various each authorisation included all the main thera­ marketing authorisations for the anti-ulcer peutic indications for which Wellcome had drug Ranitidine, also marketed under the obtained authorisation in the United Kingdom brand name 'Zantac'. up to that time.

24. On 26 July 1996 Wellcome lodged an 26. During that period, Glaxo filed new data application for judicial review of the MCA's in order to extend the initial clinical indica-

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THE QUEEN v THE MEDICINES CONTROL AGENCY, EX PARTE GENERICS (UK) AND OTHERS

tions and recommended dosing schedules. which were compromised by an agreement Glaxo's research and development costs for with the MCA in terms similar to those Ranitidine amounted to several million pounds relating to Captopril. per year. For example, in order to extend the indications for Ranitidine tablets to cover the treatment of duodenal ulcers, the results of clinical trials involving over 2 200 patients were filed at a total estimated direct expense of UKL 1.326 million.

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OPINION OF MR RUIZ-JARABO — CASE C-368/96

oesophagitis, the Zollinger-Ellison syndrome point 8(a)(iii) of the second paragraph of and the following conditions where reduction Article 4. As a result, Generics amended its of gastric secretion and acid output is desir­ application for judicial review, removing all able: the prophylaxis of gastrointestinal haem­ references to Ranitidine. orrhage from stress ulceration in seriously ill patients, the prophylaxis of recurrent haem­ orrhage in patients with bleeding peptic ulcers and before general anaesthesia in patients con­ sidered to be a risk of acid aspiration (Men- delson's syndrome), particularly obstetric patients during labour.' 30. On 16 August 1996 Glaxo commenced proceedings for judicial review of the MCA's decision which, under point 8 of the second paragraph of Article 4 of Directive 65/65, granted authorisations to second applicants, without Glaxo's consent for marketing, in respect of recommended clinical indications Those indications corresponded to those and recommended dosage schedules for Ran­ appearing in the United Kingdom registration itidine tablets which had been approved in for Ranitidine from 1984/1985 to 1988/1989. the Community in earlier authorisations granted less than 10 years previously on the basis of data submitted by Glaxo.

31. In order to determine the three sets of 29. On 29 September 1995 Generics lodged a proceedings pending before it concerning Cap­ second application for judicial review (the topril, Aciclovir and Ranitidine, the High same as for Captopril) of the MCA's decision Court considered it necessary to seek a pre­ refusing to grant it marketing authorisations liminary ruling from the Court of Justice on for indications which had not been approved the following five questions: in the Community for 10 years.

(d) some other category of indications, and if so which? (a) all indications for which product A is currently authorised in the relevant Member State at the date of the appli­ cation made in relation to product B; or (3) May product b be authorised in accor­ dance with point 8(a)(iii) of the second paragraph of Article 4 of Directive 65/65/EEC (as amended) in respect of:

(b) only those indications for which product A has been authorised in the EU in accordance with Community (a) all dosage forms and/or doses and/ provisions in force for 6 or 10 years; or dosage schedules for which or product A is currently authorised in

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the relevant Member State at the date lation been in force at the time of the application made in relation to the dosage form and/or dose and/ product B; or or dosage schedule in question was added by variation to an existing authorisation; or

(b) only those dosage forms and/or doses and/or dosage schedules for which product A has been authorised in the EU in accordance with Community provisions in force for 6 or 10 years; or (d) some other category of dosage forms and/or doses and/or dosage schedules, and if so which?

32. By its first question, the High Court asks the Court of Justice to specify which criteria are decisive in determining when two medic­ inal products are essentially similar, for the purposes of applying point 8(a)(iii) of the second paragraph of Article 4 of Directive 35. The latter interpretation of the term 'essen­ 65/65, and to state whether the national tially similar' is the one which I consider to authorities empowered to grant marketing be appropriate, for the reasons which I set authorisations have a margin of discretion in out below. making that assessment.

37. I consider that those Council minutes — Bioequivalence between the two medicinal contain an appropriate enumeration of the products, demonstrated where necessary criteria which may be used to determine essen­ by appropriate bioavailability studies. tial similarity as between two medicinal prod­ Point E of part 4 of the Annex to Direc­ ucts. Those criteria are as follows: tive 75/318, as amended by Directive 91/507, states that an assessment of bio­ availability is to be undertaken where nec­ essary to demonstrate bioequivalence for the medicinal products referred to in point 8(i), (ii) and (iii) of the second paragraph — Qualitative and quantitative composition of Article 4 of Directive 65/65/EEC. The in terms of active principles. That compo­ bioequivalence test generally provides the sition is clearly described in the Annex to best way of establishing therapeutic equiv­ Directive 75/318, as amended by Direc­ alence between two medicinal products 16 tive 91/507/EEC. Essential similarity as having the same active principles and the between two medicinal products depends same pharmaceutical form, since the excipi­ only on their active principles and neither ents and form of preparation may have an the constituents of the excipient nor those impact on their therapeutic effects. of the external covering of the medicinal products are relevant.

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THE QUEEN v THE MEDICINES CONTROL AGENCY, EX PARTE GENERICS (UK) AND OTHERS

whether, accordingly, a marketing authorisa­ Any substance or combination of substances tion may be obtained under the simplified which may be administered to human beings procedure. The fact that indications, routes of or animals with a view to making a medical administration and dosage schedules for two diagnosis or to restoring, correcting or modi­ medicinal products coincide is not relevant in fying physiological functions in human beings determining whether they are essentially sim­ or in animals is likewise considered a medicinal ilar, because such coincidence would make product.' the medicinal products identical and would preclude recourse to the simplified procedure for a marketing authorisation for generic medicinal products whenever the innovative medicinal product underwent changes, albeit of inconsiderable extent, as regards its indica­ The case-law of the Court of Justice has made tions, routes of administration and dosage it clear that the 'presentation' criterion used schedules. in the first subparagraph of that provision is designed to catch not only medicinal prod­ ucts having a genuine therapeutic or medical effect but also those that arc not sufficiently effective or which do not produce the effect which their presentation might lead one to 19 expect. It may therefore be inferred that the word 'presented' cannot be regarded as including indications as a component of the 39. Recourse to indications and dosage sched­ definition of medicinal products. ules as a criterion for determining essential similarity between two medicinal products finds no support in either Article 1 or Article 4a of Directive 65/65.

40. Having regard to the foregoing consider­ ations, I am of the opinion that two medicinal products are essentially similar where they have the same qualitative and quantitative composition in terms of active principles, their pharmaceutical form is the same and, To allow the competent authorities of the where necessary, their bioequivalence has been Member States a margin of discretion in deter­ demonstrated by means of appropriate bio­ mining essential similarity between two medic­ availability studies. inal products would also make it more dif­ ficult to apply the procedure for mutual recognition of marketing authorisations granted by Member States, established by Directive 93/39.

The use of those three objective criteria to determine essential similarity between two medicinal products for the purposes of applying point 8(a)(iii) of the second para­ graph of Article 4 of Directive 65/65 enables The second, third and fourth questions the simplified procedure for the grant of mar­ keting authorisations for generic medicinal products to be applied uniformly throughout the Community.

41. By its second, third and fourth prelimi­ nary questions, the High Court asks the Court Moreover, those criteria limit the margin of of Justice to determine the extent to which a discretion available to the competent authori­ marketing authorisation may be granted for a ties of the Member States when determining generic medical product which is essentially whether two medicinal products are essen­ similar to an original medicinal product autho- tially similar in order to grant an authorisa­ tion for a generic medicinal product, on the basis of documentation submitted earlier for a marketing authorisation for the original 21 — Scotia Pharmaceuticals, cited above, paragraph 24, and Case C-210/94 Smith & Nephew and Primecrown [1996] ECR medicinal product. In the same sense, it is 1-5819, paragraph 30.

The MCA adopts an intermediate position, taking the view that the marketing authorisa­ tion for the generic medicinal product will extend to all therapeutic indications autho­ rised for the essentially similar original medic­ inal product, both the initial indications and The undertakings specialising in the produc­ those introduced subsequently for which the tion of innovative medicinal products con­ 10-year period has not expired, except where sider that a marketing authorisation for a those modifications constitute an innovation generic medical product essentially similar to of considerable therapeutic importance. In its an original medicinal product authorised in view, an innovation displays such importance the Community or in a Member State should where it requires a fresh application for a extend only to the therapeutic indications, marketing authorisation under Annex II to routes of administration and dosage schedules Regulation No 541/95. which have been authorised for at least 10 years. In their opinion, the period of protec­ tion of 10 years must apply also to all new indications for the original medicinal product which were introduced after the issue of the marketing authorisation for it and for which the said protection period has not expired.

42. Directive 65/65, as amended by Directive 87/21, provides no direct and clear answer to the questions submitted by the High Court, a fact which accounts for the differing inter­ pretations referred to above. The interpreta­ The undertakings producing generic medicinal tion to be adopted of point 8(a)(iii) of the products consider that the marketing autho­ second paragraph of Article 4 of Directive risation for those medicinal products extends 65/65 will, however, have extremely far- to all indications, routes of administration and reaching economic repercussions on the mar­ dosage schedules authorised for the essen­ keting of medicinal products in the Commu­ tially similar original medicinal product up to nity and the development of the the very moment when authorisation is applied pharmaceutical industry as a whole.

46. The essential purpose pursued by Direc­ tive 65/65 and all the subsequent measures amending and implementing it is to safeguard 23 44. Point 8(a)(iii) of the second paragraph of public health. That purpose is achieved prin­ Article 4, inserted in Directive 65/65 by Direc­ cipally by the control mechanism of the autho­ tive 87/21, introduced a third way of obtaining risations which must be issued by the com­ a marketing authorisation for generic medic­ petent national authorities before any inal products, under the simplified procedure, medicinal product is marketed. Thus, the first which makes it unnecessary to incur the recital in the preamble to Directive 87/21 research costs involved in riling the results of states: pharmacological and toxicological tests and clinical trials, since those tests and trials were described previously in connection with the marketing authorisation for an essentially similar original medicinal product. This form of application has become the one most used to obtain marketing authorisations for generic '... point 8 of the second paragraph of Article medicinal products, since the other two pos­ 4 of Council Directive 65/65/EEC, as last sibilities (consent from the undertaking amended by Directive 83/570/EEC, provides holding the marketing authorisation for the that various types of proof of the safety and original medicinal product and reference to efficacy of a proprietary medicinal product may be put forward in an application for

22 — See the Opinion of Advocate General Léger in Scotia Phar- maceuticals, cited above, point 9 et seq. 23 — First recital in the preamble to Directive 65/65.

50. The importance of experience as a deci­ sive criterion in the achievement of medicinal innovations was highlighted by many Renais­ 25 sance researchers, who emphasised the role 48. The safeguarding of public health also played by the passage of time in relation to accounts for the last part of point 8(a)(iii) of the discovery not only of new remedies but the second paragraph of Article 4 of Direc­ also of new therapeutic properties of existing tive 65/65, which requires the undertaking remedies. The idea of progress is inseparable manufacturing the generic medicinal product from scientific advances relating to health. to submit the results of pharmacological and toxicological tests and clinical trials when applying for a marketing authorisation for indications, routes of administration or dosage 25 — N. Monardes, La Historia medicinal de les cosas que se traen de nuestras Indias Occidentales (1565/1574), Ministerio de schedules different from those authorised for Sanidad y Consumo, Madrid, 1989, attaches importance in the introduction to his work to 'the many things that there the essentially similar original medicinal arc in diverse parts of the world which were unknown until the present time; they were unknown in ancient times, but product marketed for more than 6 or 10 years time, which is the discoverer of all things, has shown them in the Community. to us' (pp. 92 and 93). In the chapter devoted to 'sangre de drago', used to treat stomach disorders and to strengthen the gums, he refers to the 'thousand follies' spoken by 'the ancients, whether Greek, Roman or Arab', which have been rendered outmoded by what 'time, which is the discoverer of all things, has revealed to us and taught us' (pp. 218 and 24 — Scotia Pharmaceuticals, cited above, paragraph 17. 219).

51. In the Commission's travaux prepara- 26 toires prior to the adoption of Directive 87/21 it is clearly stated that one of the objec­ tives pursued is the protection of research and innovation in the pharmaceutical sphere. Article 52(4) of the 1973 Munich Convention The Commission laid stress on the costs which on the Grant of European Patents does not had to be borne by innovative undertakings regard as patentable inventions those relating to obtain the initial marketing authorisation to methods for treatment of the human or for a medicinal product and stated that cer­ animal body by surgery or therapy or diag­ tain national authorities too easily allowed nostic methods practised on the human or recourse to the simplified procedure, based animal body. Nevertheless, Article 54(5) allows on references to scientific literature, by under­ the patenting of substances for use in the takings producing generic medicinal prod­ preparation of medicinal products, and there­ ucts. According to the Commission, that prac­ fore the latter can benefit from the 20-year tice was prejudicial to innovative undertakings protection provided for in the convention. In holding marketing authorisations for original the domestic laws of the Member States there medicinal products. has been a similar trend and they recognise

26 — COM(84) 437finalof 25 September 1984, paragraphs 14 and 27 — See, in that connection, P. Leardini, 'Brevets', Joly Com- 15. munautaire, Paris, December 1997.

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28 — The present situation has been described by Advocate Gen­ eral Fennelly in his Opinion in Joined Cases C-267/95 and C-268/95 Merck and Beechimi [1996] ECR I-6285, points 75 to 87. 29 — Council Regulation (EEC) No 1768/92 of 18 June 1992 con­ the cernine creation of a supplementary protection certifi­ cate for medicinal products (OJ 1992 L 182, p. 1). 31 — See Council Directive 86/609/EEC of 24 November 1986 on 30 — This regulation has been interpreted by the Court of Justice the approximation of laws, regulations and administrative in, inter alia. Case C-350/92 Spain v Council [1995] ECR provisions of trie Member States regarding the protection of I-1985; Case C-181/95 Biogen [1997] ECR I-357, and Case animals used for experimental and other scientific purposes C-110/95 Yamanouchi Pharmaceutical [1997] ECR I-3251. (OJ 1986 L 358, p. 1).

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OPINION OF MR RUIZ-JARABO — CASE C-368/96

Furthermore, it is conducive to the protec­ tion of public health for a generic medicinal product to be marketed on the basis of refer­ Marketing authorisations for generic medic­ ence to all the therapeutic indications, routes inal products, applied for under that provi­ of administration and dosage schedules sion, will cover all indications, routes of accepted by the competent authorities for the administration and dosage schedules autho­ essentially similar original medicinal product. rised up to that time for the essentially similar In that way the maximum therapeutic yield is original medicinal product marketed in the obtained from generic medicinal products. Community for 6 or 10 years. Nevertheless, new indications for the original medicinal product, which have been authorised for at least 6 or 10 years, will also enjoy the 6 or 10 year protection period where they constitute therapeutic innovations of considerable impor­ tance. New routes of administration and dosage schedules for the original medicinal Finally, the proposed interpretation prevents product do not constitute significant thera­ innovative undertakings which obtain a mar­ peutic innovations and, consequently, are not keting authorisation for an original medicinal covered by that protection period. product from resorting to an obstructive

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THE QUEEN v THE MEDICINES CONTROL AGENCY, EX PARTE GENERICS (UK) AND OTHERS

In my opinion, there is a significant innova­ tion only where the undertaking holding the marketing authorisation for the original 59. The interpretation suggested is also in medicinal product obtains a subsequent autho­ harmony with the rule requiring non- risation for a new indication of great thera­ repetition of tests on persons and animals peutic importance. In such a case, it is appro­ unless strictly necessary. New therapeutic priate to apply the 6 or 10 year protection indications, routes of administration and/or period to the new indication in order to pro­ dosage schedules authorised for an original tect the innovation achieved by the pharma­ medicinal product are supported by the tests ceutical undertaking, because it is thereby carried out by the innovative undertaking and possible to amortise the substantial invest­ it is not advisable that they be repeated merely ments normally required to achieve a signifi­ because there has not been a time lapse of cant innovation. A new indication of consid­ more than 6 or 10 years since the authorisa­ erable therapeutic importance will normally tion of those modifications. require new pharmacological and toxicological tests and clinical trials of a scope similar to those needed to obtain a marketing authorisa­ tion for any new medicinal product.

60. The encouragement of pharmaceutical innovation and research, and the protection of the industrial and commercial property of innovative undertakings, are also ensured to the proper extent by the interpretation which 61. The application of that interpretation of I propose of point 8(a)(iii) of the second point 8(a)(iii) of the second paragraph of paragraph of Article 4 of Directive 65/65. Article 4 of Directive 65/65 calls for details of

There is no basis for the view taken by the MCA that those major variations constitute new indications of great therapeutic impor­ tance which require additional protection by 62. For that purpose, the MCA relied upon virtue of point 8(a)(iii) of the second para­ Regulation No 541/95 as a basis for deter­ graph of Article 4 of Directive 65/65. In the mining when a new therapeutic indication is first place, Annex II to Regulation No 541/95 of great importance. The Commission, Glaxo, states that 'This Annex is without prejudice Wellcome, Squibb, Generics and the Swedish to the provisions of Article 4 of Directive and Danish Governments consider recourse 65/65/EEC...'. Secondly, a therapeutic inno­ to that regulation to be inappropriate. vation is not a relevant factor for the purpose of classifying variations as being major or minor. Finally, that regulation is of a merely formal nature and does no more than harmo­ nise administrative practices applicable to changes in the terms of marketing authorisa­ tions, which renders it inapplicable so far as concerns determining the substantive condi­ tions to be met for the grant of authorisations In my opinion, it is not possible to derive for generic medicinal products under the from Regulation No 541/95 criteria by which abridged procedure. to determine whether or not a new indication for an original medicinal product is of great therapeutic importance. That regulation is a measure of a procedural nature which supple­ ments Articles 7 and 7a of Directive 65/65, which were amended by Directive 93/39, con­ cerning procedures for mutual recognition of marketing authorisations for medicinal prod­ ucts issued by the competent authorities of 63. In my opinion, it is for the national com­ the Member States. Regulation No 541/95 petent authorities to determine in each spe­ extends the provisions on mutual recognition cific case whether a new indication for an to changes in the terms of marketing autho­ original medicinal product authorised for less risations for medicinal products. That regula­ than 6 or 10 years constitutes a therapeutic tion distinguishes between minor variations innovation of great significance deserving sup­ and major variations. The latter, enumerated plementary protection in relation to an essen­ in Annex II to the regulation, involve a radical tially similar generic medicinal product. In alteration of the terms of the marketing autho­ carrying out that assessment, the competent

— The possibility that the new therapeutic 32 indication may be eligible for a patent under the Munich Convention or the national legislation of a Member State. The initial therapeutic indications for an orig­ 65. This question raises the question of the inal medicinal product can be patented possible invalidity of point 8(a)(iii) of the and it is also possible to patent subse­ second paragraph of Article 4 of Directive quent therapeutic indications provided that 65/65 on the ground that it breaches the prin­ they constitute a novelty deriving from ciples of protection of innovation, non­ inventive effort and are capable of being discrimination, proportionality and/or respect put to practical therapeutic use. The eli­ for property. gibility for patent protection of a new therapeutic indication for an original medicinal product is indicative of the ther­ apeutic innovation embodied in it and for that reason is a factor to be taken into account in determining whether or not 66. In its order for reference, the High Court does not indicate the reasons which prompted it to raise the possibility that the provision in question may be invalid as being incompat­ 32 — The Court ofJustice has considered the relationship between ible with those general principles of Commu­ patents and marketing authorisations from another stand­ point in Case C-316/95 Generics [1997] ECR 1-3954. nity law. Personally, I perceive nothing in

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Point 8(a)(iii) of the second paragraph of Article 4 of Directive 65/65 provides for a simplified marketing authorisation procedure 68. As regards respect for property, the Court for generic medicinal products essentially sim­ of Justice has held that it is a right upheld in ilar to original medicinal products that have the Community legal order but one which been marketed for 6 or 10 years, in which use may be subject to restrictions which corre­ is made of the results of the pharmacological spond to objectives of general interest and do and toxicological tests and clinical trials sub­ not constitute, having regard to the aim pur­ mitted by the innovative undertaking. That sued, a disproportionate and intolerable inter­ procedure is in conformity with the principle ference impairing the very substance of the of proportionality since it is appropriate in rights guaranteed. 37 The use, upon expiry of order to ensure the protection of public health, the protection period of 6 or 10 years, by non-repetition of tests on persons and ani­ undertakings producing generic medicinal mals, and protection of innovation and phar­ products of the results of the pharmacological and toxicological tests and clinical trials sub­ mitted by the innovative undertakings in order 33 — See paragraphs 51 to 55 above. 34 — Case 203/86 Spain v Council [1988] ECR 4563, paragraph 14, and Case C-22/94 Irish Farmers Association and Others v Minister for Agriculture, Food and Forestry, Ireland, and the Attorney General [1997] ECR 1-1809, paragraph 34. 35 — Joined Cases C-296/93 and C-307/93 France and Ireland v 36 — See points 45 to 56 above. Commission [1996] ECR I-795, paragraph 30; Case C-280/93 37 — Case 5/88 Wachauf [1989] ECR 2609, paragraph 18; Case Germany v Council [1994] ECR I-4973, paragraph 90, and C-177/90 Kühn [1992] ECR I-35, paragraph 16, and Case Case C-331/88 Fedesa and Others [1990] ECR I-4023, para­ C-280/93 Germany v Council [1994] ECR I-4973, paragraph graph 14. 78.

(2) The competent national authorities enjoy no margin of discretion in assessing essential similarity between two medicinal products for the purposes of point 8(a)(iii) of the second paragraph of Article 4 of Directive 65/65 of the Council of 26 January 1965 on the approximation of provisions laid down by law, regu­ lation or administrative action relating to proprietary medicinal products.

(3) Marketing authorisations for generic medicinal products will extend to all indi­ cations, routes of administration and dosage schedules authorised until that time for the essentially similar original medicinal product which has been mar­ keted in the Community for 6 or 10 years. Nevertheless, new therapeutic indi­ cations for the original medicinal product, authorised less than 6 or 10 years earlier, will enjoy protection for a period of 6 or 10 years where they constitute therapeutic innovations of great significance.

(4) Commission Regulation (EC) No 541/95 of 10 March 1995 concerning the examination of variations to the terms of a marketing authorisation granted by

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OPINION OF MR RUIZ-JARABO — CASE C-368/96

a competent authority of a Member State has no bearing on the application of point 8(a)(iii) of the second paragraph of Article 4 of Directive 65/65.