C-94/98

OPINION OF M R LA PERGOLA — CASE C-94/98

OPINION OF ADVOCATE GENERAL LA PERGOLA delivered on 19 May 1999 *

I — The factual and legislative context of provisions of the Treaty concerning the free the main proceedings and the questions movement of goods. referred

* Original language: Italian. which was expressly stated to be 'to safe- 1 — OJ, English Special Edition 1965-66, p. 20. The amend- ments to the directive which are relevant here are those guard public health'. 3 In particular, the made by the following instruments: Second Council Direc- Directive extensively harmonised the rules tive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative on quality, safety and efficacy which must action relating to proprietary medicinal products (OJ 1975 L 147, p. 1 3 ; see Articles 35 and 36); Council Directive be observed by the authorities responsible 83/570/EEC of 26 October 1983 amending Directives 65/65/EEC, 75/318/EEC and 75/319/EEC on the approx-

ing to proprietary medicinal products (OJ 1993 L 214, p. 22; see Article 1). Directive 93/39 established, with effect from 1 January 1995, a decentralised procedure for mutual 3. No medicinal product may be offered for recognition of national marketing authorisations, together sale in a Member State without a marketing with binding arbitration by the Community in the event of disagreement between Member States (see Article 4, second paragraph, subparagraph 1 1 , Article 7(2) and 7(a) of Directive 65/65 and Articles 8 to 15c of Directive 75/319). The independent national procedures remain, but as from 2 — The abovementioned Directives 89/341 and 93/39 (see 1 January 1998 (the end of the transitional period for the footnote 1 above), however, were adopted on the basis of new procedure) they are strictly limited to the initial phase Article 100a of the EC Treaty (now, after amendment, (issue of the marketing authorisation by the 'reference Article 95 EC). Member State' and to medicinal preparations not marketed 3 — See the preamble to Directive 65/65 (cited above, footnote in more than one Member State. 1, and relevant part of text), in particular the first recital.

authorisation ('MA') having first been necessary to assess the product in question, issued in respect of it by the competent including any unfavourable information. authorities of that State in accordance with Moreover, in order to monitor the positive the Directive (see the first paragraph of and negative effects after issue of the MA, Article 3 of the Directive). 4An application the holder must notify the competent for an MA for a medicinal product, lodged authorities of all changes in data, new by the person responsible for placing the information not contained in the initial product on the market, must contain the application and pharmacovigilance reports information and be accompanied by the (see below, footnote 25 and relevant part of documents particularised in Article 4 of the text). Directive, even if the medicinal product in question is already the subject of an MA issued by the competent authority in another Member State. 5According to the annex to Directive 75/318/EEC, 6the par- ticulars and documents accompanying an 4. The competent authority may refuse to application for an MA submitted in accor- grant an MA only if, after examining the dance with Article 4 comprise the follow- application, it determines that: (a) the ing parts: (i) a summary of the dossier, (ii) information and documents supplied by chemical, pharmaceutical and biological the applicant are irregular or incomplete, tests of the medicinal products, (iii) tox- (b) the product is harmful under normal icological and pharmacological tests, and conditions of use, (c) its therapeutic effi- (iv) clinical documentation. The applica- cacy is lacking or has not been sufficiently tion must contain all the information substantiated by the applicant, or (d) the qualitative and quantitative composition of the product is not as declared (see Arti- cles 5 and 21 of the Directive).

tests). 6 — Council Directive 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). In order to facilitate the issue of marketing authorisations for the same medicinal product in several 5. Article 11 (in conjunction with Arti- Member States, Directives 75/318 ana 75/319 (cited in footnote 1 above) harmonised the methods for controlling cle 21) of the Directive goes on to say that medicinal products put on to the market, in particular by an MA may be suspended or revoked on requiring tne national authorities to examine applications for authorisation on the basis of the protocols described in the following grounds only: (a) the product the annex referred to in the text. That annex was replaced by Commission Directive 91/507/EEC of 19 July 1991 proves to be harmful in normal conditions amending the annex to Directive 75/318/EEC (OJ 1991 of use or (b) its therapeutic efficacy is L 270, p. 32) in order to bring it into line with technical progress. lacking or (c) its qualitative and quantita-

tive composition is not as declared by the the Court, the fact that parallel importers applicant, (d) the information in the file is quite often offer the goods at a price lower incorrect or has not been amended in than that charged by the duly appointed accordance with Article 9a (concerning importer 'should. . . encourage the public changes to methods of preparation and health authorities not to place parallel control to bring them into line with scien imports at a disadvantage, since the effec tific and technical progress) or (e) checks tive protection of health and life of humans have not been carried out on the ingredi also demands that medicinal preparations ents, intermediate products and finished should be sold at reasonable prices'. 7 products in accordance with the methods According to that judgment, it must be described by the applicant. borne in mind that, in the sphere of free movement of medicinal products, the requirement of protecting public health

More specifi that derogation are fulfilled, including the cally, the issue in the main proceedings is requirement that any harm done by the whether and to what extent revocation of national measure restricting intra-Commu- the original MA may affect the freedom of economic operators outside the official distribution channels of the holder of the MA to carry out parallel imports of a different variant of the product from other Member States where it is sold at lower prices than those charged in the importing country. 7 — See Case 104/75 De Peijper [1976] ECR 613, paragraph 25. 8 — According to the said Article 36, 'the provisions of Arti cles 28 and 29 shall not preclude prohibitions or restrictions

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7. In De Peijper, the Rotterdam Kanton- MA for medicinal products subject to the rechter (district public prosecutor) had condition that the parallel importer must commenced criminal proceedings for infringement of Netherlands health legisla- tion against an unauthorised importer of 10 — In De Peijper, the Netherlands judge asked the Court (I) certain medicinal products, who was oper- whether Article 30 of the EC Treaty was to be interpreted as meaning that a national measure which makes the grant ating without having in his possession the of the MA for a medicinal product subject to the condition file (concerning the medicinal product in that the parallel importer must provide the competent authority with documents identical to those already lodged the abstract) and the so-called 'records' by the manufacturer or his exclusive concessionaire is compatible with that article, where: (i) the medicinal (relating to checks of individual batches of product in question, prepared in accordance with uniform imported goods) for the products in ques- methods and having a homogeneous qualitative and quantitative composition, is marketed in one or more

. . [had the]. . . exclusive the appointed distributor for the Netherlands and the one intention of using the differences. . . in order to prevent or marketed by the parallel importer had common origins: impede the possibility of the parallel importation' (see De they were produced — in Switzerland and the United Pei/per, cited in footnote 7, paragraphs 10, 11 and 33). Kingdom — by manufacturers belonging to the same group of companies. 11 — See De Peijper (cited in footnote 7 above), paragraph 18.

supply to the competent authority in the medicinal product are produced and mar- Member State of importation documents keted under the same name in more than identical to those already lodged by the one Member State and that (ii) the differ- manufacturer or its exclusive concessio- ences between the variants, regarding the naire; in such circumstances, the latter manufacturing process or the qualitative would be allowed to monopolise imports and quantitative composition of the pro- and marketing of the medicinal product in duct in question, have an impact on its question by refusing to produce documents therapeutic effect. Only in such circum- relating to the product in general or to a stances, according to the Court, would

it of 16 October 1981 by the European paration in question and considered to be absolutely Parliament, the Commission subsequently necessary for the purpose of checking that the medicinal preparation is effective and not harmful, it is clearly decided to withdraw that proposal. The unnecessary, in order to protect the health and life of humans, for the said authorities to require a second trader principles inspiring the document were who has imported a medicinal preparation which is in nevertheless published in the form of guide- every respect the same to produce the abovementioned particulars to them again' (paragraph 2 1 , emphasis added). lines for Member States and the relevant As regards, on the other hand, the obligation to produce documents like the records for each batch of products economic operators. 15 I think it is relevant imported in parallel, the Court observed that it is undeniable that the national competent authorities must to consider that Commission initiative at be able to verify, with absolute certainty and at any time, this stage because, as is stated in the order whether or not a particular batch conforms with the information given in the file. However, according to the for reference, great inspiration was drawn Court, even where the administrative rules in force in the importing Member State include the requirement that a parallel importer must prove that an imported batch conforms to the description of the medicinal product, there

paragraphs 29 and 27). C 115, p. 5).

10. This Court delivered another important judgment concerning parallel imports of medicinal products in 1996, that is to say a little more than 20 years after De Peijper. The High Court of Justice (the court from which today's questions emanate) had asked the Court of Justice to provide the requisite guidance for interpretation of the Directive, and of the obligations associated with MAs for medicinal preparations, in order to determine disputes between Smith 9. MAL 2 (PI) defines 'parallel imports' as & Nephew Pharmaceuticals ('S&N') and meeting two requirements: the product is the MCA and the competing company the subject of an MA in the United King- dom and the applicant seeks to import from another Member State a version of that 17 — Under Paragraph 4 of MAL 2 (PI), the medicinal product sought to be imported by way of parallel import must be: product which already has an MA issued by (a) a product which is to be imported from a Member

Directive. To qualify for that procedure, are in force. If either ceases to be valid for any reason (for the medicinal product must satisfy several example, it may lapse or be revoked) the PL(PI) also ceases to be valid. Paragraph 21 of MAL 2 (PI) provides, finally, conditions, in particular it must have been that the normal arrangements apply with regard to variations to a PL(PI) made at the request of the licence made by or under licence to the manufac- holder. The competent authority verifies that the terms of turer who made the product covered by the the authorisation still conform with the relevant provisions of the applicable MA and notifies the PL(PI) holder of any action necessary as a result of a variation to the United Kingdom reference MA. The holder of a PL(PI) is required to notify the competent authority of any variation to the 16 — See Notes on Application for Product Licences (Parallel Community MA that comes to his attention and is Importing) (Medicines for Human Use), as amended required to obtain a variation to the PL(PI) before he can (hereinafter 'MAL 2 (PI)'). market the varied product in the United Kingdom.

Primecrown, and secondly, between Prime- one — in which the medicinal product crown and the MCA. 18 Those disputes manufactured in the importing State and arose from the grant in August 1993 of a the one brought in as a parallel import, PL(PI) to Primecrown for a medicinal even though manufactured under licence by product manufactured in Belgium, where independent companies, ultimately origi- it was covered by an MA. The product of nated from the same licensor — the rule in Belgian origin had the same name and was De Peijper should apply (see point 7 above) manufactured under a licensing agreement otherwise such agreements could lead to concluded with the same licensor for a partitioning of the national markets of the product for which S&N had held a United various Member States. 21 That case-law, Kingdom MA since January 1991. 19 said the Court in paragraph 26 of the Because the PL(PI) had been granted to judgment, is applicable not only where the Primecrown on the false assumption that proprietary medicinal product covered by there existed between S&N and Marion an original MA in the importing State and Merrel Dow Belgium the corporate link the one brought in as a parallel import are required for application of the simplified identical in all respects, but also where the procedure (see above, footnote 17 and two medicinal products 'have at least been relevant part of the text), the licence was manufactured according to the same for- subsequently annulled by the MCA after it mulation, using the same active ingredients discovered the error. The Court held, first, and... have the same therapeutic effects'. that the obligation of an applicant for an Consequently, the Court concluded that the MA to produce the necessary information competent authority of a Member State — and documents prescribed by the Directive if it concludes that a medicinal product in order to verify that a medicinal product covered by an MA in another Member is effective and harmless is justified only for State and a medicinal product for which it medicinal products which are being put on has already issued an MA, manufactured the market for the first time. That obliga- by independent companies under agree- tion cannot, however, be relied on by the ments with the same licensor, although competent authority of a Member State in not identical in every respect, are at least order to protect public health in relation to manufactured in accordance with the same a medicinal product already covered by an formulation and using the same active MA in another Member State and of which ingredients and having the same therapeu- the import into the first country constitutes tic effects — must extend the benefit of that a parallel import of a product already MA to the imported product. That obliga- covered by another MA.20 According to tion becomes inoperative only if there are the Court, therefore, in a case such as this reasons relating to effective protection of human life and health. Where, on the other hand, the competent national authority reaches the conclusion that the medicinal product intended to be imported on a

parallel basis does not satisfy the criteria dential annex to the order for reference mentioned here — and cannot, therefore, ('the confidential annex'). The 'new Zimo be regarded as already on the market in the vane' contains the same active ingredient importing Member State — a new MA will and has the same therapeutic effect as the become necessary, which may be granted 'old Zimovane' but is prepared by a only in accordance with the conditions laid different production process using different down in Articles 3 and 4 of the Directive. 22 excipients (an excipient is a inert substance used as a diluent or vehicle for a pharma ceutical product). In order to place the new version of the product on the market in the United Kingdom, in July 1996 RPR, after

In 1989 and 1993 the MCA granted May & Baker on the basis of which the old version of ('M&B') a total of five marketing author Zimovane had been distributed in the isations for the United Kingdom 2 3 for United Kingdom, and of (unused) author zopiclone, a hypnotic used for the short- i s a t i o n s n u m b e r s 0 0 1 2 / 0 1 6 3 and term treatment of insomnia, marketed in 0012/0164. Thus, as from 1 August 1996, most of the Member States under the brand RPR ceased to market, directly or under name Imovane and in the United Kingdom licence, the old version of Zimovane in the under the name Zimovane. Under an United Kingdom and distributes only the agreement concluded in 1992, M&B new version, in the form of 3.75 mg or 7.5 appointed Rhône-Poulenc Rorer (the two mg tablets. The old version of Zimovane companies being hereinafter jointly referred nevertheless continues to be distributed in to as 'RPR') as its agent for the production the other Member States (with the excep and distribution of certain medicinal pro tion of Portugal). However, it is RPR's ducts, including Zimovane. In 1996 RPR intention to replace the old version by the improved, following research and develop new version of the medicinal product, as it ment for more than three years, costing has done in the United Kingdom, in step around UKL 1 500 000, a new version of with the issue of marketing authorisations Zimovane which is particularly beneficial by the competent authorities in the Mem for public health, described in the confi ber States. 2 4 RPR considers that it would be committing a criminal offence if it distributed the new version of Zimovane 22 — See paragraph 1 of the operative part of the judgment in the same case. 'It would therefore be contrary to [the Directive]' the Court observed, '.

Luxembourg, Finland and the Netherlands) and in tion number 0012/0162 was in fact used. Norway.

'1. In a case where medicinal product X is sought to be imported from Member State A into Member State B, is it permissible for the person who pro­ poses to place the imported product upon the market in Member State Β to 12. In accordance with paragraph 12 of seek and obtain a marketing authorisa­ MAL 2 (PI) (see footnote 17 above), seven tion from the competent authority in authorisations for parallel imports of the Member State Β without complying old version of Zimovane into the United with the requirements of the Council Kingdom, which had previously been Directive 65/65/EEC (as amended) if: granted to five operators, became invalid as from 31 July 1996 as a result of revocation of the 'mother' authorisation, directed by the MCA at the request of RPR (i) medicinal product X is the subject (see point 11 above). Upon being notified of a marketing authorisation by the MCA (in accordance with paragraph granted in Member State A and 21 of MAL 2 (PI)), the holders of the was the subject of a marketing authorisations in question therefore applied authorisation which has ceased to for the variations needed to 'anchor' them have effect in Member State B; and to a valid reference MA, specifically MA number 0012/0259. The MCA decision to grant or maintain in force, under the abridged procedure, the seven authorisa­ (ii) medicinal product X has the same tions for the old version of Zimovane (in active ingredients and therapeutic 7.5 mg tablets) is one of the two measures effect as medicinal product Y, but challenged by RPR in the main proceed­ is not manufactured according to ings. The second measure contested by RPR the same formulation as medicinal is the MCA's decision to grant to each of product Y; and three other operators, again under the MAL 2 (PI) procedure, an authorisation for parallel imports of the old version of Zimovane (in 7.5 mg tablets) into the (iii) medicinal product Y is the subject United Kingdom from Spain. of a marketing authorisation granted in Member State B, but is not the subject of a marketing authorisation granted in Member State A; and

2. To what extent is it relevant to the answer to Question 1 that: (vi) the competent authority considers that the prohibition on imports of product X from Member State A would have the effect of partition­ ing the market; and/or (i) the marketing authorisation for medicinal product X ceased to have effect in Member State Β as a result of voluntary surrender on the part of the person to whom it had been granted; and/or (vii) the competent authority considers that there are no grounds within Article 36 of the EC Treaty which would justify a prohibition on imports and sales of product X?' (ii) the formulation of medicinal pro­ duct Y was developed and intro­ duced in order to provide a benefit to public health which medicinal product X (manufactured accord­ ing to a different formulation) does not provide; and/or II — The submissions of the parties to the main proceedings and the observations of the Member States and the Commission

(iii) that benefit to public health would not be achieved if product X and product Y are both on the market in Member State Β at the same 14. RPR states that the Community provi­ time; and/or sions on parallel imports of medicinal

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RHÔNE-POULENC RORER AND MAY & BAKER

public health, even if construed in the Article 29d of Directive 75/319/EEC and manner contended for by RPR and Article 10 of Directive 65/65/EEC). 25 described in the confidential annex, does Those obligations moreover do not apply not call for a drastic measure such as the to parallel importers either, regardless of total blocking of parallel imports of the old whether those economic operators actually version of the product. Notwithstanding possess the relevant data. The Commission the formal revocation of the 'mother' therefore submits that the MCA is no authorisation, the MCA still has at its longer in a position to assess the safety of disposal all the data, documents and details the version of the medicinal product prescribed by Article 4 of the Directive to imported into the United Kingdom on the monitor the efficacy and harmlessness of basis of the most up-to-date scientific data. the medicinal product intended to be the The United Kingdom authorities contend subject of parallel imports. The MCA states that compliance with the pharmaceutical that it received them from RPR in connec- monitoring requirements mentioned by the tion with the procedure for the issue of an Commission could be ensured (i) by virtue MA for the new version of the product in of RPR's obligation to provide up-to-date question, which contains the same active information regarding the new version of ingredients and has the same therapeutic Zimovane or (ii) even if it were conceded effects. that the two variants of the medicinal product constituted different products, by means of cooperation with the other national authorities in accordance with the criterion laid down by the Court in paragraph 27 of the De Peijper judgment, through access to the documents and data produced by RPR or by other companies in its group for the old version in the Member

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RHÔNE-POULENC RORER AND MAY & BAKER

30 — The United Kingdom authorities seem, therefore, implicitly to admit in principle that in the event of revocation (or non-renewal) of an original MA or voluntary surrender not followed by an application for an MA for a different variant of the medicinal product in question, it is not in any event permissible to authorise on the basis of MAL 2 (PI) parallel imports of the product from other Member States in which it is covered by valid authorisations, with 2 1 . In that light, the interpretation the result that it is necessary for the MCA to undertake the procedure for complete evaluation provided for by the requested by the High Court to enable it Directive.

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preparation. If on the other hand the rule in that diversity from the legal point of view. question were to be applied literally to In the first case it is legitimate to ask — as every minor change in the formulation of a Advocate General Mayras did in the medicinal product, even those having no past — 'what interest a manufacturer of impact on its therapeutic effects, it could pharmaceutical products can have in man- lawfully result in the stopping of parallel ufacturing in different forms a medicinal imports of the earlier version of the pro- preparation intended to be marketed under

Peijper. Therefore, the rule referred to is obligatory under specific national health applicable only where the medicinal pro- rules. But even allowing for these rules, the duct brought in by way of parallel import question often remains unanswered, unless and the product covered by an MA in the the view is taken that the differences in importing Member State are not manufac- question were introduced for purely com- tured by companies in the same group. mercial reasons with a view to dividing up the market and taking advantage of a profitable situation'.

22. The objections raised are of some merit and substance. They bring to light the fundamental difference between a 'De 31 — See the Opinion of Advocate General Mayras in De Peijper Peijper type' situation (product of the same [1976] ECR 641, particularly at 650 and 651.

marketed in the importing Member State. clinical studies and to change the formula­ Whilst pointing out that the solution of tion (more precisely, the excipients used) of having the requirements of the free move­ the Ditropan manufactured in the United ment of goods take precedence over those Kingdom as compared with that produced of public health is a little dangerous, in the United States by the licensor com­ Advocate General Mayras took the view pany, Marion Merrel Dow (and in Belgium that in circumstances like those of De by one of its subsidiaries), in view of the Peijper — having regard to the strong need to prove to the MCA that the product temptation facing manufacturers to exploit was not potentially carcinogenic. 33 differing legislation in order to make huge profits and isolate markets — that solution involves a minor risk worth running. 3 2 That solution is clearly based on the proposition — which I think reflects the technical and scientific thinking of the time — that the fact that two medicinal products have the same therapeutic effect in itself implies that they are also the same as far as monitoring users' safety is con­ 24. The Smith Šč Nephew judgment also cerned. recognised, at least by implication, that even where the differences of formulation as between the variants of a product are not reflected by differences in their respective therapeutic effects, those differences still fall within the range of factors of which the competent authority (subject to review by the national courts) must take into account when monitoring the quality, safety and efficacy of the variants in question for the purpose of classifying them as similar or different medicinal products with a view to authorising their marketing. 3 4 As stated by 23. In its judgment in Smith Sc Nephew, the plaintiffs in the main proceedings, however, the Court took the view, if I am France and the Commission, the principle not mistaken, that it is wholly legitimate that the competent authority is required to for individual national licensees not linked take account not only of the therapeutic by membership of the same group of efficacy but also of the composition in companies to decide to manufacture med­ terms of active ingredients and excipients icinal products under licence according to of the various versions of a given medicinal different specifications, in particular as product can be inferred from numerous regards the excipients employed, without pieces of legislation. I have already stated it being possible to attribute that fact, even merely by way of presumption, to a con­ certed intent to isolate the national mar­ 33 — Smith Sc Nephew, cited in footnote 18 above, paragraph 9. kets. It should be remembered that S&N 34 — It should be borne in mind that the 'criteria of quality, had been required to carry out additional safety and efficacy' are those on which, in the interests of public health and for the benefit of users of the medicinal products, the decision of the competent national authority on an application for an MA must be exclusively based (see the third recital in the preamble to Directive 93/39, cited in 32 — Ibid. footnote 1 above).

that the competent national authorities are actual manufacturing formulation must required to examine applications for give a quantitative breakdown of all the authorisation on the basis of the protocols substances used, including the excipients described in the abovementioned annex to (although for the latter approximate terms Directive 75/318 (see footnote 6 above and may be used 'in so far as the pharmaceu- the relevant part of the text). Pursuant to tical form makes this necessary'). More- those protocols, the qualitative particulars over, the identification and dosage of the of all the constituents of the proprietary excipient constituents are part of the infor- medicinal product — which an applicant mation relating to controls carried out on for an MA must supply in accordance with the finished product which the applicant is point 3 of the second paragraph of Arti- required to provide under point 7 of the cle 4 of the Directive — consist in the second paragraph of Article 4 of the Direc- designation or description not only of the tive. 36 active ingredients and of the constituents of the pharmaceutical form to be administered to the patient but also of the constituents of the excipients, whatever their nature or the quantity used (including colouring matter, preservatives, stabilizers, thickeners, emul- sifiers, flavouring and aromatic sub-

Under Article 4b, when the marketing authorisation is issued the person responsible for placing that product on the market is to be informed, by the competent authorities of the Member State concerned, of the summary of the product 36 — See the Annex to Directive 75/318 (cited in footnote 6), characteristics as approved by them. The competent paragraph 3, part 2, points A.1.1., A.4.1, B.1 and E.1.3. authorities are to take all necessary measures to ensure 37 — See European Commission, The rules governing medicinal that the information given in the summary is in conformity products in the European Union, Volume UIC, Guidelines with that accepted when the marketing authorisation is on the quality, safety and efficacy of medicinal products issued or subsequently. for human use.

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The 'essentially similar' to an original medicinal national court indicated in its first question product for the purposes of admitting the (in subparagraph (iv)) that the holders of second applicant for an MA to the abridged the MAs and the producers of the old and p r o c e d u r e p r o v i d e d for by Arti- new versions of Zimovane are members of cle 4.8(a)(iii) of the Directive is precisely a the same group of companies.

38 — Bio-availability means the proportion of active substance product. And that should always be the or therapeutic moiety (for example salts, esters, etc.) case: regardless of any differences in the delivered from a pharmaceutical form which reaches the central circulatory system of a patient to whom the medicinal product is administered. Differences in the excipients and/or in the production process for two medicinal products may lead to differing rates of dissolu- 39 — See Case C-368/96 The Queen ν The Licensing Authority, tion or absorption. Two medicinal products, which are ex parte Generics [1998] ECR I-7967, paragraphs 32, 33 'pharmaceutical equivalents' (that is to say they contain and 36. The abovementioned point 8(a) of the second the same quantity of the same active substance in the same paragraph of Article 4 provides for three alternatives in dosage forms) or 'pharmaceutical alternatives' (having the which the applicant for an MA is not required to furnish same therapeutic moiety but in a different chemical form the results of pharmacological and toxicological tests or of or dosage form) are said to be bio-equivalent if their clinical trials. The abridged procedure referred to in the respective bio-availabilities are so similar as to give rise to text, however, 'in no way relaxes the requirements of safety essentially identical effects in terms of efficacy and safety. and efficacy which must be met by medicinal products' (see In practice, the proof of bio-equivalence between pharma- Case C-440/93, cited in footnote 5 above, paragraph 17). ceutical equivalents or alternatives is also the most A generic medicinal product is a copy of an innovative adequate proof of therapeutic equivalence as between the medicinal product whose formulation can be reproduced medicinal products in question, provided that they contain by other manufacturers and which can be sold under the excipients generally recognised as safe and bear the same same name at a price that is usually lower than that of the instructions for use (ibid.). original product.

excipients used or in the 'recipe' and manufacturer appears to be based on whatever the reasons for such differences. genuine and objectively verifiable reasons I cannot agree with the United Kingdom's relating to the protection of public health. view. It should also be noticed mutatis mutandis that even according to Smith &c Nephew the obligation of the competent national authority of a Member State to extend the original MA granted in that State so as to cover a variant of a medicinal product that is (i) imported as a parallel import from another Member State in which its market- ing is duly authorised and (ii) is identical to the one authorised in the importing Mem- 26. As Advocate General Mayras noted in ber State according to the three parameters De Peijper, in this area it is necessary to laid down by the Court, does not apply seek a delicate balance between the oppos- ing requirements of free movement of where there are countervailing considera- goods and protection of public health, tions relating to effective protection of the between the aim of eliminating any State health and life of humans. 40 measure which reserves imports of a med- icinal product to operators belonging to the official distribution network of the holder of the MA and the aim of ensuring strict monitoring of the efficacy and harmlessness of the products available on the national market, even though in some cases there may be duplication of the relevant admin- istrative checks. Freedom of parallel imports must be duly safeguarded — and affects the applicability of the derogation under Article 36 of the EC Treaty to the restrictive measure, consisting of the need for an MA for the import of medicinal products which are already covered by an MA in another Member State — where it is 27. I conclude therefore that the presump- apparent or can be inferred that the man- tion established in De Peijper (differences ufacturer of the different variants of a of formulation without any impact on medicinal product intends partitioning the therapeutic effect = same level of quality Community market and, in particular, and safety for users of the various national isolating the national markets in which it variants = intention of the manufacturer to might be able to charge the highest prices. divide up the market) is to be seen as a That freedom should not however be seen rebuttable presumption (juris tantum), as a dogma. In my view, therefore, the which can be set aside in the face of competent State authority will be required evidence to the contrary. If the manufac- to treat as different products, for the turer is able to demonstrate to the full purposes of MAs for the national market, satisfaction of the competent national the variants of a medicinal product with different formulations where recourse to 40 — See Smith &c Nephew, cited above (footnote 18), para- that policy of diversification by the sole graph 1(a) of the operative part.

authority that the difference of formulation remainder of the Community (see point 16 is a response to genuine and objective above). concerns of public health — and only in such circumstances — it will have to be concluded that the variants of the medic- inal product in question are different pro- ducts and that, in consequence, that author- ity does not possess for both certain information prescribed by the directive. I would add that the factors which the competent authority (and possibly the courts) of the importing Member State must take into account when assessing the gravity and reality of the grounds of protection of public health relied on by the manufacturer to justify the differences 28. If it should be proved that the varia- of formulation of the diverse variants tions in the formulation of the different include the possibility that the version variants are intended to protect public withdrawn from the national market in health, there must be declared lawful under question may nevertheless still being man- Article 36 of the EC Treaty any refusal by ufactured and marketed by the same firm the competent national authority to allow or by a company in the same group in other under the simplified ad hoc procedure the

The solution the United Kingdom market from the which I suggest here, moreover, makes it

possible to avoid a situation where the that that administration does not appear in producers of a given medicinal product are principle to dispute that checks on the able, by deliberately introducing some safety of medicinal products placed on the marginal change to the formulation of the market must extend to adverse side effects product, to block parallel imports of a under actual conditions of use. That is, not variant of that product which has been by chance, a fundamental principle forming proved safe, as is feared by the United part of the Community rules on this matter. Kingdom authorities. It is relevant to note the obligations men- tioned by France and the Commission in their observations, which derive from the rules on the exchange of information and cooperation between national authorities in the area of pharmacovigilance.41 In parti- cular, Article 29a of Directive 75/319, under which the Member States are

I humans within its territory (see footnote 28 agree, finally, with the submissions of the above and relevant part of text). The MCA French authorities to the effect that the has decided that there are no doubts as to competent authority or the national courts the harmlessness of the medicinal product of the importing Member State, in analys- at issue under normal conditions of use and ing the level at which the protection of that the reasons set out in the confidential human life and health is ensured in national annex, which in 1996 prompted RPR to law, are required to establish whether the market the new version of Zimovane and at precautionary principle and the principle the same time to withdraw the earlier that preventive action should be taken — version from circulation, cannot be linked principles analogous to those which, under with the general interest in ensuring the the Treaty, apply to the action of the protection of human health, as that concept Community authorities — are applic- is understood in United Kingdom law. able. 42 However, the applicability of Article 36 of the EC Treaty to this case was ruled out by the MCA because of the alleged absence of concrete proof of the factual circumstances giving rise to the concerns regarding the protection of public health mentioned by RPR rather than because it considered in 41 — See Articles 29a to 29i of Directive 75/319, introduced by the abstract that the reasons relied on by Article 3(3) of Directive 93/39 (cited in footnote 1 above). 42 — It follows from the principles mentioned in the text that, the plaintiffs were inadequate. Without where there are uncertainties regarding the existence or scope of risks to consumers' health, the institutions may prejudice to the fact that the final word adopt protective measures without having to wait until the remains with the national court when reality and seriousness of those risks have become fully apparent (see Case C-157/96 R v MAFF, ex parte National evaluating the views of the defendant Farmers' Union and Others [19981 ECR I-2211, para- graph 63, and Case C-180/96 United Kingdom v Commis- administration, I would observe, in passing, sion [1998] ECR I-2265, paragraphs 99 and 100).

(ii) medicinal product Y is the subject of an MA granted in Member State Β but not of an MA granted in Member State A,

(iii) the marketing authorisations mentioned under (i) and (ii) above were granted to different members of the same group of companies and the manufacturers of the medicinal products X and Y are also members of that group of companies,

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OPINION OF MR LA PERGOLA — CASE C-94/98

(iv) the formulation of medicinal product Y was developed and introduced in order to secure a benefit for the health of humans which medicinal product X (produced according to a different formulation) does not provide,

(v) it is not possible to secure that public health benefit where medicinal product X and medicinal product Y are available at the same time on the market of Member State B, and