Octapharma France SAS v Agence nationale de securite du medicament et des produits de sante (ANSM) and Ministere des affaires sociales et de la sante [2013] EUECJ C-512/12 (07 November 2013)

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Agence nationale de sécurité du médicament et des produits de santé (ANSM) and

(Approximation of legislation – Directive 2001/83/EC – Directive 2004/27/EC – Directive 2002/98/EC – Scope of application – Labile blood products – Plasma prepared by a method involving an industrial process – Simultaneous or exclusive application of Directive 2001/83 (as amended by Directive 2004/27) and Directive 2002/98 – Article 168(4) TFEU and Member State discretion to maintain more stringent protective measures for blood and blood derivatives)

1. The present reference for a preliminary ruling from the Conseil d’État (France), seeks to ascertain which European Union legal regime applies to a plasma product called ‘Octaplas’. This product is prepared by a method involving an industrial process (‘industrially prepared plasma’) and is used in blood transfusions. Octapharma France SAS (‘Octapharma’), which is the producer and distributor of the product, and the French Republic take differing views, and these have an impact on the conditions under which Octaplas may be administered and commercialised in the internal market.

2. The problem in a nutshell is as follows. Does Article 3(6) of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, (2) as amended by Directive 2004/27, (3) preclude the Agence nationale de sécurité du médicament et des produits de santé (the National Agency for Medicines and Health Product Safety, ‘ANSM’) from classifying an industrially prepared plasma known as ‘plasma SD’, which includes Octaplas, (4) as a labile blood product?

II – The dispute in the main proceedings and the questions referred for a preliminary ruling

3. By a decision of 20 October 2010 the Director General of the Agence française de sécurité sanitaire des produits de santé (AFSSAPS), an organisation which later became the ANSM, classified Octaplas as a labile blood product. Octapharma has brought proceedings in the Conseil d’État seeking, inter alia, the annulment of the decision of 20 October 2010, an order compelling the Director General of the AFSSAPS to apply Article 1 of Directive 2004/27 within three months of the judgment of the Conseil d’État, and a similar order compelling the French State to see to the proper transposition of Directive 2004/27.

4. L’Établissement français du sang (EFS) (‘the French Blood Agency’) is a public law body which has a monopoly under French law for organising in the national territory the collection of blood and the preparation and distribution of labile blood products. Thus, the classification of plasma SD as a labile blood product means that it is to be administered and distributed exclusively by the French Blood Agency. The decision of 20 0ctober 2010 was made even though Octapharma has been able to market Octaplas as a medicinal product in around 30 countries worldwide and in the European Union, including in Austria, Belgium, Germany and the United Kingdom.

5. Octapharma argues that the authorisation for marketing of industrially prepared plasma is governed exclusively by Council Directive 2001/83, as amended by Directive 2004/27, and that industrially prepared plasma should rather be categorised as a medicinal product.

6. The French authorities contest this, principally on the basis that the marketing in France of industrially prepared plasma is governed exclusively by another European Union instrument, namely, Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC. (5) Furthermore, they invoke the entitlement of Member States under Article 168(4) TFEU to maintain and introduce ‘more stringent protective measures’ than those passed by the EU legislature under the ordinary legislative procedure with the purpose of setting standards of ‘quality and safety of organs and substances of human origin, blood and blood derivatives’.

7. In the light of the foregoing, the Conseil d’État has referred the following questions for a preliminary ruling:

8. Octapharma, the French Government and the Commission presented written observations. All participated at the hearing which took place on 10 July 2013.

9. This case entails a competition between two legal regimes, namely, that applicable to medicinal products under Directive 2001/83 as amended by Directive 2004/27 on the one hand, and that applicable to human blood and blood components under Directive 2002/98 on the other. The latter contains free standing provisions setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components. Directive 2004/27 also contains an important amendment to Directive 2001/83 which I will discuss below. The discretion afforded to Member States under Article 168 TFEU to introduce ‘more stringent protective measures’ than those supplied by EU legislation steps in as a further complication to the resolution of the dispute.

10. Directive 2001/83 entered into force in December 2001. (6) Even prior to its amendments by Directive 2004/27, it contained specific provisions appertaining to blood and plasma. Recital 17 states that it is necessary to adopt specific provisions for inter alia ‘medicinal products based on human blood or human plasma’, while recital 28 states, inter alia, that authorisation to market medicinal products derived from human blood or human plasma is subject to demonstration by the manufacturer of his ability to maintain batch to batch consistency, along with demonstration of the absence of specific viral contamination, to the extent that the state of the technology permits.

11. Community harmonisation with respect to blood and blood products was achieved by Directive 2002/98, which also amended Directive 2001/83. Pursuant to its Article 32, Directive 2002/98 was to be transposed by the Member States by 8 February 2005.

12. Recital 3 of Directive 2002/98 states that the ‘quality, safety and efficacy requirements of proprietary industrially-prepared medicinal products derived from human blood or plasma were ensured through Directive 2001/83 …’ but adds that the ‘specific exclusion of whole blood, plasma and blood cells of human origin from that Directive, however, has led to a situation whereby their quality and safety, in so far as they are intended for transfusion and not processed as such, are not subject to any binding Community legislation’. Recital 3 adds, inter alia, that it was essential that ‘Community provisions should ensure that blood and its components are of comparable quality and safety throughout the blood transfusion chain in all Member States’.

13. Recital 4 of Directive 2002/98 recalls that Directive 2001/83 refers to measures to be taken by Member States to prevent the transmission of infectious diseases in respect of blood or blood components as a starting point for the manufacture of proprietary medicinal products. Recital 5 adds that Directive 2001/83 should be amended in order to ensure that there is an equivalent level of safety and quality of blood components, whatever their intended purpose, by imposing technical requirements for the collection and testing of all blood and blood components including starting materials for medicinal products.

14. In consequence, Article 31 of Directive 2002/98 replaced the text of Article 109 of Directive 2001/83 with the following:

For the collection and testing of human blood and human plasma, Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC shall apply.’ (7)

15. Further, Directive 2002/98 introduced several provisions aimed at laying down standards of quality and safety of human blood and of blood components, in order to ensure a high level of human health protection (see Article 1).

16. Article 2(1) of Directive 2002/98 states that the directive applies to the ‘collection’ and ‘testing’ of human blood and blood components whatever their intended purpose and to their processing, storage and distribution when intended for transfusion, while Article 2(2) states that where blood and blood components are collected and tested for the sole purpose and exclusive use in autologous transfusion and are clearly identified as such, the requirements to be complied with in respect thereof shall be in accordance with those referred to in Article 29(g).

17. Three definitions appearing in Article 3 of Directive 2002/98 assist in determining the scope of Directive 2002/98. Pursuant to Article 3(a) ‘blood’ shall mean whole blood collected from a donor and processed either for transfusion or for further manufacturing. Pursuant to Article 3(b) ‘blood component’ shall mean a therapeutic constituent of blood (red cells, white cells, platelets, plasma) ‘that can be prepared by various methods’ while Article 3(c) states that ‘blood product’ shall mean any therapeutic product derived from human blood or plasma.

18. Finally, Article 4(2) of Directive 2002/98 preserves Member State national competence to apply more protective regulation. It states that the directive shall not prevent a Member State from maintaining or introducing in its territory more stringent protective measures which comply with the provisions of the Treaty.

19. Directive 2001/83 was amended extensively by Directive 2004/27. According to recital 7 of Directive 2004/27 the definitions and scope of Directive 2001/83 needed to be clarified ‘as a result of scientific and technological progress’. Recital 7 also stated, inter alia, that in order to take into account the emergence of new therapies and the growing number of so-called ‘borderline’ products between the medicinal sector and other sectors, the definition of ‘medicinal product’ needs to be modified so as to ‘avoid any doubt as to the applicable legislation when a product, whilst fully falling within the definition of a medicinal product, may also fall within the definition of other regulated products.’

20. Pursuant to Article 2(2) of Directive 2001/83, as amended by Directive 2004/27, in cases of doubt ‘where, taking into account all its characteristics, a product may fall within the definition of a “medicinal product” and within the definition of a product covered by other Community legislation the provisions of this Directive shall apply’.

21. Finally, notwithstanding the aforementioned amendment to Article 109 of Directive 2001/83 that appeared in Directive 2002/98, Directive 2004/27 amended Article 3 of Directive 2001/83 so that its paragraph 6 now provides that Directive 2001/83 shall not apply to whole ‘blood, plasma or blood cells of human origin, except for plasma which is prepared by a method involving an industrial process’. Before its amendment, Article 3(6) of Directive 2001/83 provided that the directive did not apply to whole ‘blood, plasma or blood cells of human origin’.

22. To my mind the answer to the first question is straightforward. Article 3(6) of Directive 2001/83, as amended by Article 1 of Directive 2004/27, states that Directive 2001/83 ‘shall not apply to … [w]hole blood, plasma or blood cells of human origin, except for plasma which is prepared by a method involving an industrial process’. The plain and literal meaning of the revised Article 3(6) of Directive 2001/83 leaves no room for doubt. Industrially prepared plasma is to be governed by Directive 2001/83.

23. In my opinion this means that it is not strictly necessary for the Court to look any further (8) and consider for example the purpose of the amendment to Article 3(6) of Directive 2001/83 wrought by Directive 2004/27. However, even if it were, as pointed out by the Commission at the hearing, and in its written observations, the intention of the EU legislature, in passing Directive 2004/27, was to subject plasma prepared by a method involving an industrial process to the Community rules relating to medicinal products for human use, that is Directive 2001/83. This objective is reflected in particular in recital 7 of Directive 2004/27.

24. In my opinion, it is not necessary, therefore, to consider Article 2(2) of Directive 2001/83 as amended by Directive 2004/27, and the course to be followed ‘in cases of doubt’, (my emphasis) and in which a product ‘may fall within the definition of a “medicinal product” and within the definition of a product covered by other Community legislation’. But even if it were, both the plain meaning of Article 3(6) of Directive 2001/83, as amended by Directive 2004/27, and the purpose of Article 2(2) of Directive 2001/83, as amended by Directive 2004/27, gives priority to Directive 2001/83, as amended, over Directive 2002/98.

25. Without Article 3(6) of Directive 2001/83, as amended by Directive 2004/27, Directive 2002/98 would apply to the collection and testing as well as processing, storage and distribution, when intended for transfusion, of industrially prepared plasma. This would follow from Article 2(1) of Directive 2002/98 when read together with the definitions contained in Article 3, points b and c, thereof.

26. This leads to the question concerning the exact role of Directive 2002/98 with respect to industrially prepared plasma. As was pointed out by the Commission at the hearing, the passerelle between Directive 2002/98 and Directive 2001/83, as amended by Directive 2004/27, is Article 109 of Directive 2001/83 which was amended by Article 31 of Directive 2002/98. It states that Directive 2002/98 applies to collection and testing of human blood and human plasma. This encompasses human blood and human plasma, as regulated by Directive 2002/98, and plasma prepared by a method involving an industrial process, the latter being either a blood component or a blood product as defined in Article 3, point b and c of Directive 2002/98, but otherwise falling within the scope of Directive 2001/83, as amended.

27. It is true that Directive 2002/98 contains no express exception with respect to plasma prepared by methods involving an industrial process, and that its Article 2(1) refers to both ‘collection and testing’ and ‘their processing, storage, and distribution when intended for transfusion’. (9) However, in my opinion this is insufficient to preclude the applicability of Directive 2001/83, as amended by Directive 2004/27, to industrially prepared plasma, even when it is intended for transfusion, especially given that Directive 2004/27 was adopted after Directive 2002/98.

28. As was pointed out by Octapharma at the hearing, the case to hand does not concern the collection or testing of industrially prepared plasma. It is rather concerned with its commercialisation (that is production, authorisation and distribution). Thus, given the respective scopes ratione materiae of Directive 2001/83, as amended by Directive 2004/27, and Directive 2002/98, the latter is not pertinent to the resolution of the dispute.

29. With regard to the argument of the French Government to the effect that Article 168(4)(a) TFEU entitles it to adopt ‘more stringent protective measures’ than those provided by the EU legislature with respect to standards ‘of quality and safety’ of ‘organs and substances of human origin, blood and blood derivatives’, I agree with the observations made by the Commission at the hearing relating to the relevance of Article 168 TFEU. The proviso appearing in Article 168(4)(a) is only applicable in the context of Directive 2002/98, given that it is a measure of minimum harmonisation. This means that the entitlement in the hands of Member States to maintain or introduce ‘more stringent protective measures which comply with the provisions of the Treaty’ which appears in Article 4(2) of Directive 2002/98 is confined to matters falling within that directive. But, as I have already mentioned, the dispute to hand falls outside of the scope ratione materiae of Directive 2002/98.

30. As was also pointed out by the Commission at the hearing, and given that Directive 2001/83 as amended by Directive 2004/27 establishes complete harmonisation of the rules relevant to the placing on the market of medicinal products for human use, (10) industrially prepared plasma included, Member States are no longer allowed to adopt stricter national measures.

31. I would make one final observation with respect to question 1. While I have concluded that industrially prepared plasma falls within the scope ratione materiae of Directive 2001/83 as amended by Directive 2004/27, even if it is intended for transfusion, the national court has referred no question on whether the specific product Octaplas is a ‘medicinal product’ within the meaning of Directive 2001/83. In my opinion, this appears to be the locus of the arguments of the French Government, in that they seem to suggest that blood intended for transfusion cannot be a medicinal product.

32. While, and for the reasons I have given, this position cannot be accepted, for the sake of completeness I would simply note that assessment of whether or not ‘plasma SD’ in general, and the product Octaplas in particular, is indeed a medicinal product is a matter for the national referring court. It has to solve this issue with due account taken, inter alia of Articles 1 and 2(1) of Directive 2001/83, as amended by Directive 2004/27, the Court’s case-law on the meaning of ‘medicinal products for human use’, (11) and the judgment in this case.

33. Given my answer to the first question, it is not necessary to give a separate answer the second preliminary question. This is so because I have concluded that Article 4(2) of Directive 2002/98 is confined to the activities falling within the scope ratione materiae of that directive, which does not cover commercialisation of industrially prepared plasma.

34. Finally, in the event that the Court accepts the arguments of Octapharma, the French Government asks the Court to exercise its discretion to suspend the temporal effects of the judgment. It submits that important legislative modifications and administrative and practical arrangements will be needed in order to avoid the risk to public health, particularly to patient safety, resulting from the immediate application of Directive 2001/83, as amended by Directive 2004/27, to plasma prepared by a method involving an industrial process and destined in France for transfusion to patients. These products will need to be administered through a different system from that applicable to plasma derived from human blood without involving an industrial process.

35. Moreover, the French Blood Agency does not have the necessary authorisations to act as a pharmaceutical establishment, and it would not have the right to prepare or deliver, for the purposes of transfusion, plasma prepared by a method involving an industrial process if the temporal effect of the judgment of the Court were not suspended. This means that plasma of this kind held in storage by the French Blood Agency would not be usable, even in cases of surgical urgency.

36. The French Government has stated that one quarter of the plasma supplies in France are made up of plasma prepared by a method involving an industrial process. That being so, serious disruption to plasma supplies in France may result if there is no suspension of the temporal effects of the Court’s judgment.

37. Finally it has been pointed out that the co-existence in French law of two monitoring systems, one for blood and the other for medicinal products, may result in further complications in terms of patient safety and public health. Amendment to the relevant legislative acts may ultimately be required in order to coordinate the two systems.

38. However, as worthy and important as these factors may be, they reflect considerations broader than the narrow legal question that the Court is being asked to consider in this case: namely whether plasma which is prepared by a method involving an industrial process falls within the scope of Directive 2001/83, as amended by Directive 2004/27, Directive 2002/98 or both. It is worth noting that the rapporteur public suggested that the Conseil d’État might refer a question to the Court of Justice inviting it to suspend the temporal effects of its judgment, but this suggestion was not followed.

39. In my opinion considerations of legal certainty recognised in the Court’s case-law do not warrant the suspension of the temporal effects of the Court’s judgment. As I have explained, after the passage of Directive 2004/27 through the EU legislative process, there was no warrant for the French authorities, or indeed those of any other Member State, to maintain the view that the marketing authorisation of plasma prepared by a method involving an industrial process and intended for transfusion was not governed by Directive 2001/83, as amended by Directive 2004/27. It is only exceptionally, in application of the general principle of legal certainty, which is inherent in the European Union legal order, that the Court may decide to restrict the right to rely upon a provision which it has interpreted, with a view to calling into question legal relationships established in good faith. (12)

40. It is true that it was put to the Court in Inter-Environnement Wallonie and Terre wallonne and accepted that the objective of a high level of protection of the environment ‘may be better achieved … by maintaining the effects of the annulled order during a short period necessary for its redrafting rather than by retroactive annulment’. (13) This judgment, which was relied on by the French Government before this Court, and referred to by the rapporteur public before the Conseil d’État, authorised the referring national court to make use of provisions of national law empowering it to maintain certain effects of a Member State decision that was adopted in breach of an obligation contained in a directive. (14) This authorisation was subject to strict and detailed conditions elaborated by the Court.

41. However, in my opinion, in the present case the Court lacks detailed and concrete information relating to the relevant circumstances in France, and the consequences flowing from the different courses of action that might be taken. Such information was provided by the national court in Inter-Environnement Wallonie and Terre wallonne in the express context of a reference for a preliminary ruling on whether it could, on the basis of national law, suspend the annulment of a Member State measure that had already been found to have been taken in breach of EU law. (15)

42. In the case to hand, there is a dearth of concrete information concerning, inter alia, the practical effects of the three month time limit for the adoption of a new decision by the Director General of AFSSAPS (now ANSM) and for the transposition of Directive 2001/83, as amended by Directive 2004/27, by the French State as has been requested in the action brought by Octapharma before the Conseil d’État. Nor is there any information on whether or not the French Blood Agency would be able to establish itself in the medicinal products sector, and whether it would be possible to remedy any of the difficulties referred to above by recourse to Article 126a of Directive 2001/83. (16) Finally, there was no discussion either of whether or not there could be any expedition of the relevant legislative and administrative procedures. (17)

43. Moreover, simple suspension of temporal effects would in this case lead to a situation in which Octapharma would be deprived, and illegally, of the possibility of asking for marketing authorisation for Octaplas as a medicinal product, should the national court find that it fulfils the definition of a medicinal product. This outcome would conflict with the general principle according to which the Member States are required to nullify the unlawful consequences of a breach of EU law. (18)

44. In my opinion, while the relevant arms of the French Government will need to act swiftly to avoid the broader social and public health consequences of releasing industrially prepared plasma from the monopoly of the French Blood Agency, so that authorisation for its marketing can be processed by reference to the pertinent EU law provisions, these considerations remain distant from the discrete issue of product classification that the Court is being asked to assess.

45. In the light of the foregoing, I would respond to the questions referred by the Conseil d’État as follows:

3 – Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community Code relating to medicinal products for human use (OJ 2004 L 136, p. 34).

4 – According to the case file, this product is produced when fresh plasma is frozen and viruses are attenuated by solvent detergents.

7 – The original text of Article 109 of Directive 2001/83 stated as follows: ‘1. In respect of the use of human blood or human plasma as a starting material for the manufacture of medicinal products, Member States shall take the necessary measures to prevent the transmission of infectious diseases. In so far as this is covered by the amendments referred to in Article 121(1), as well as the application of the monographs of the European Pharmacopoeia regarding blood and plasma, these measures shall comprise those recommended by the Council of Europe and the World Health Organisation, particularly with reference to the selection and testing of blood and plasma donors. 2. Member States shall take the necessary measures to ensure that human blood and human plasma donors and donation centres are always clearly identifiable. 3. All the safety guarantees referred to in paragraphs 1 and 2 must also be given by importers of human blood or human plasma from third countries.’

8 – See point 37 in my Opinion in Case C-85/11 Commission v. Ireland [2013] ECR I-0000; Case C-582/08 Commission v United Kingdom [2010] ECR I-7195, paragraph 51, and my opinion in that case at point 52.

10 – Case C-84/06 Antroposana and Others [2007] ECR I-7609, paragraphs 40 to 42. At paragraph 42 the Court held that Directive 2001/83 ‘established a complete regulatory framework for registration and market authorisation procedures in respect of medicinal products for human use’. See also Case C-185/10 Commission v Poland [2012] ECR I-0000.

11 – E.g. Case C-308/11 Chemische Fabrik Kreussler [2012] ECR I-0000; Case C-27/08 BIOS Naturprodukte [2009] ECR I-3785; Case C-140/07 Hecht-Pharma [2009] ECR I-41; Antroposana and Others; Case C-369/88 Delattre [1991] ECR I-1487; Joined Cases C-211/03, C-299/03 and C-316/03 to C-318/03 HLH Warenvertrieb and Orthica [2005] ECR I-5141; Case C-219/91 Ter Voort [1992] ECR I-5485.

12 – Case C-292/04 Meilicke and Others [2007] ECR I-1835, paragraph 35. See also Joined Cases C-338/11 to C-347/11 Santander Asset Management SGIIC and Others [2012] ECR I-0000, paragraphs 56 to 63.

13 – Case C-41/11 Inter-Environnement Wallonie and Terre wallonne [2012] ECR I-0000, paragraph 55.

14 – Namely Directive 2001/42/EC of the European Parliament and of the Council of 27 June 2001 on the assessment of the effects of certain plans and programmes on the environment (OJ 2001 L 197, p. 30).

15 – This had occurred in Joined Cases C-105/09 and C-110/09 Terre wallone and Inter-Environnement Wallonie [2010] ECR I-5611.

16 – According to Article 126a of Directive 2001/83, as amended by Directive 2004/27, in ‘the absence of a marketing authorisation or of a pending application for a medicinal product authorised in another Member State in accordance with this Directive, a Member State may for justified public health reasons authorise the placing on the market of the said medicinal product’.

17 – According to Annex I, Part III, point 1.1, to Directive 2001/83, as amended by Commission Directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use (OJ 2003 L 159, p. 46) for medicinal products derived from human blood or plasma, the dossier requirements for starting materials may be replaced by a Plasma Master File certified in accordance with that Part. Where a Plasma Master File corresponds only to blood/plasma-derived medicinal products, the marketing authorisation of which is restricted to a single Member State, the scientific and technical evaluation of the said Plasma Master File shall be carried out by the national competent authority of that Member State.

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Court of Justice of the European Communities (including Court of First Instance Decisions)