CELEX: 62001CJ0106
Language: en
Date: 2004-04-29 00:00:00
Title: Judgment of the Court (Sixth Chamber) of 29 April 2004. # The Queen, on the application of Novartis Pharmaceuticals UK Ltd v The Licensing Authority established by the Medicines Act 1968 (acting by the Medicines Control Agency). # Reference for a preliminary ruling: Court of Appeal (England and Wales) (Civil Division) - United Kingdom. # Medicinal products - Marketing authorisation - Procedure relating to essentially similar products. # Case C-106/01.

Case C-106/01
      The Queen on the application of Novartis Pharmaceuticals UK Ltd
      v
      The Licensing Authority established by the Medicines Act 1968 (acting by the Medicines Control Agency)
      (Reference for a preliminary ruling from the Court of Appeal (England and Wales) (Civil Division))
      (Medicinal products – Marketing authorisation – Procedure relating to essentially similar products)
      Summary of the Judgment
      1.        Approximation of laws – Proprietary medicinal products – Marketing authorisation – Testing of medicinal products – Examination
            on the basis of all the data in the possession of the competent authority
      (Council Directive 65/65, Arts 4.8(a)(iii) and 5, first subpara.)
      2.        Approximation of laws – Proprietary medicinal products – Marketing authorisation – Abridged procedure – Essentially similar
            products – Bioequivalent products
      (Council Directive 65/65, Art. 4.8(a)(i) and (iii))
      3.        Approximation of laws – Proprietary medicinal products – Marketing authorisation – Abridged procedure – Essentially similar
            products – Determination of the pharmaceutical form of the medicinal product – Consideration of the form in which it is presented
            and administered, including the physical form
      (Council Directive 65/65, Art. 4.8(a)(i) and (iii))
      4.        Approximation of laws – Proprietary medicinal products – Marketing authorisation – Hybrid abridged procedure – Scope – Conditions
            – Essentially similar products – Limits
      (Council Directive 65/65, Art. 4.8(a)(i), (iii) and final subpara.)
      5.        Approximation of laws – Proprietary medicinal products – Marketing authorisation – Abridged procedure – Reference product
            when considering request for authorisation – Right of competent authority to refer to data of a product authorised under the
            hybrid abridged procedure
      (Council Directive 65/65, Art. 4.8(a)(iii) and final subpara.)
      6.        Approximation of laws – Proprietary medicinal products – Marketing authorisation – Hybrid abridged procedure – Consideration
            of two requests for authorisation in respect of the same product – Requirement for different data for each request – Principle
            of non-discrimination – Infringement – Absence
      (Council Directive 65/65, Art. 4.8(a) and last para.)
      1.        In accordance with the first recital in the preamble to Directive 65/65 relating to medicinal products, as amended by Directives
         87/21, 89/341 and 93/39, the primary purpose of any rules concerning the production and distribution of medicinal products
         must be to safeguard public health. Where the competent authority of a Member State making a decision on an application for
         marketing authorisation examines the safety and efficacy of the medicinal product, it is permissible for that authority to
         take account of all data in its possession, from whatever source, to the extent that such data demonstrate that the product
         is harmful or that it lacks efficacy. Accordingly, and pursuant to the first subparagraph of Article 5 of Directive 65/65,
         an application for marketing authorisation must be refused, inter alia, where, on the basis of data in the possession of the
         competent authority, it appears that a medicinal product is harmful or lacks efficacy. Clearly the competent authority is
         not precluded from basing its refusal on data submitted by other applicants, even if that data is protected within the meaning
         of Article 4.8(a)(iii) of the Directive.
      
      (see paras 29-31)
      2.        Products cannot be regarded as essentially similar for the purposes of the application of Article 4.8(a)(i) or (iii) of Directive
         65/65 relating to medicinal products, as amended by Directives 87/21, 89/341 and 93/39, where they are not bioequivalent.
      
      (see para. 35, operative part 1)
      3.        For the purposes of the procedure laid down by Article 4.8(a)(i) and (iii) of Directive 65/65 relating to medicinal products,
         as amended by Directives 87/21, 89/341 and 93/39, in determining the pharmaceutical form of a medicinal product, account must
         be taken of the form in which it is presented and the form in which it is administered, including the physical form. In that
         context, medicinal products which are presented in the form of a solution to be mixed in a drink for administration to the
         patient and which, after mixing, form, respectively, a macroemulsion, a microemulsion and a nanodispersion, are to be treated
         as having the same pharmaceutical form, provided that the differences in the form of administration are not significant in
         scientific terms. 
      
      (see para. 42, operative part 2)
      4.        The proviso, that is, the hybrid abridged procedure laid down by the final subparagraph of Article 4.8(a) of Directive 65/65
         relating to medicinal products, as amended by Directives 87/21, 89/341 and 93/39, applies to applications for marketing authorisation
         based on Article 4.8(a)(i) or (iii).
      
      An application for marketing authorisation for a medicinal product may be made under the proviso, with reference to an authorised
         medicinal product provided that the medicinal product in respect of which marketing authorisation is sought is essentially
         similar to the authorised medicinal product, unless one or more of the differences set out in the proviso apply, as the case
         may be.
      
      (see paras 47, 55, operative part 3)
      5.        In considering an application for marketing authorisation for a new product C under Article 4.8(a)(iii) of Directive 65/65
         relating to medicinal products, as amended by Directives 87/21, 89/341 and 93/39, with reference to a product A authorised
         for more than six or 10 years, the competent authority of a Member State is entitled, with a view to granting marketing authorisation,
         to refer without the consent of the person responsible for marketing to data submitted in support of a product B which was
         authorised within the previous six or 10 years under the hybrid abridged procedure laid down by Article 4.8(a) of Directive
         65/65, with reference to product A, where those data consist of clinical trials provided in order to demonstrate that product
         B, though suprabioavailable to product A when administered in the same dose, is safe.
      
      (see para. 67, operative part 4)
      6.        In considering two hybrid applications for marketing authorisation for products B and C brought under the final subparagraph
         of Article 4.8(a) of Directive 65/65 relating to medicinal products, as amended by Directives 87/21, 89/341 and 93/39, and
         referring to product A, the competent authority of a Member State does not infringe the principle of non-discrimination where,
         as a precondition for the grant of marketing authorisation, it requires full clinical data on the bioavailability of product
         B, but, having examined the data filed in support of product B, does not require the same data for product C. 
      
      (see para. 72, operative part 5)

      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
            
            JUDGMENT OF THE COURT (Sixth Chamber)29 April 2004(1)
         
         
               (Medicinal products  –  Marketing authorisation  –  Procedure relating to essentially similar products)
               
             In Case C-106/01,
             REFERENCE to the Court under Article 234 EC by the Court of Appeal (Civil Division) (England and Wales) for a preliminary
            ruling in the proceedings pending before that court between
            
            
            
            The Queen  on the application of Novartis Pharmaceuticals UK Ltd
            
            and
            
            The Licensing Authority established by the Medicines Act 1968 (acting by the Medicines Control Agency), andSangStat UK Ltd, andImtix-SangStat UK Ltd,
             on the interpretation of Article 4.8(a) of Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions
            laid down by law, regulation or administrative action relating to medicinal products (OJ, English Special Edition 1965-1966,
            p. 20), as amended by Council Directives 87/21/EEC of 22 December 1986 (OJ 1987 L 15, p. 36), 89/341/EEC of 3 May 1989 (OJ
            1989 L 142, p. 11) and 93/39/EEC of 14 June 1993 (OJ 1993 L 214, p. 22),
            
            THE COURT (Sixth Chamber),,
            
             composed of: V. Skouris, acting for the President of the Sixth Chamber, C. Gulmann (Rapporteur), J.-N. Cunha Rodrigues, J.-P.
            Puissochet and R. Schintgen,  Judges,
            
             Advocate General: F.G. Jacobs,Registrar:  M.-F. Contet, Principal Administrator,
            
            
            after considering the written observations submitted on behalf of:
               
               –
                Novartis Pharmaceuticals UK Ltd, by I. Dodds-Smith and R. Hughes, Solicitors, D. Anderson QC, and J. Stratford, Barrister,
               
               –
                SangStat UK Ltd and Imtix-SangStat UK Ltd, by T. Cook and J. Mutimear, Solicitors,
               
               –
                the United Kingdom Government, by J.E. Collins, acting as Agent, P. Sales, Barrister and R. Singh QC, 
               
               –
                the Danish Government, by J. Molde, acting as Agent,
               
               –
                the French Government, by G. de Bergues and R. Loosli-Surrans, acting as Agents,
               
               –
                the Portuguese Government, by L.I. Fernandes, acting as Agent,
               
               –
                the Commission of the European Communities, by H.C. Støvlbæk and R. Wainwright, acting as Agents,
               
               
            
            
            
            
            after hearing the oral observations of Novartis Pharmaceuticals UK Ltd, SangStat UK Ltd and Imtix-SangStat UK Ltd, the United
               Kingdom Government, represented by K. Manji, acting as Agent, and P. Sales, the Danish Government, the Netherlands Government,
               represented by J.G.M. van Bakel, acting as Agent, and the Commission, represented by H.C. Støvlbæk and M. Shotter, acting
               as Agent, at the hearing on 7 November 2002,
            
            
            after hearing the Opinion of the Advocate General at the sitting on 23 January 2003,
         gives the following
         
         
         Judgment
         1
            
          By order of 22 February 2001, received at the Court on 5 March 2001, the Court of Appeal (Civil Division) (England and Wales)
         referred to the Court for a preliminary ruling under Article 234 EC six questions on the interpretation of Article 4.8(a)
         of Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by law, regulation or administrative
         action relating to medicinal products (OJ, English Special Edition 1965-1966, p. 20), as amended by Council Directives 87/21/EEC
         of 22 December 1986 (OJ 1987 L 15, p. 36), 89/341/EEC of 3 May 1989 (OJ 1989 L 142, p. 11), and 93/39/EEC of 14 June 1993
         (OJ 1993 L 214, p. 22, hereinafter ‘Directive 65/65, as amended’).
         
         
         
         2
            
          Those questions were raised in proceedings between Novartis Pharmaceuticals UK Ltd (‘Novartis’) and the Medicines Control
         Agency (‘MCA’) concerning the issue by the MCA of two marketing authorisations in respect of a medicinal product. 
         
         
            
               Law
            
         
         3
            
          Article 3 of Directive 65/65, as amended, requires a marketing authorisation to be obtained before a medicinal product may
         be placed on the market in a Member State.
         
         
         
         4
            
          Article 4 of the same directive provides:
         ‘In order to obtain an authorisation to place a medicinal product on the market as provided for in Article 3, the person responsible
         for placing that product on the market shall make application to the competent authority of the Member State concerned.
         …
          The application shall be accompanied by the following particulars and documents:
         …
         
         8.
            Results of:
         
         
         
          
         
            
               –
                  physico-chemical, biological or microbiological tests,
               
         
         
         
         
          
         
            
               –
                  pharmacological and toxicological tests,
               
         
         
         
         
          
         
            
               –
                  clinical trials.
               
         
         
         
               However, and without prejudice to the law relating to the protection of industrial and commercial property:
                  
               
         
         
         
            
               (a)
                  The applicant shall not be required to provide the results of pharmacological and toxicological tests or the results of clinical
                     trials if he can demonstrate:
                  
               
         
         
            
               
                  
                     (i)
                        either that the medicinal product is essentially similar to a product authorised in the country concerned by the application
                           and that the person responsible for the marketing of the original medicinal product has consented to the pharmacological,
                           toxicological or clinical references contained in the file on the original medicinal product being used for the purpose of
                           examining the application in question;
                        
                     
               
         
         
         
            
               
                  
                  
                     …
                  
               
         
         
            
            
               
                  
                  
                     
                        
                        
                           or that the medicinal product is essentially similar to a product which has been authorised within the Community, in accordance
                                 with Community provisions in force, for not less than six years and is marketed in the Member State for which the application
                                 is made; this period shall be extended to 10 years in the case of high-technology medicinal products within the meaning of
                                 Part A in the Annex to Directive 87/22/EEC or of a medicinal product within the meaning of Part B in the Annex to that directive
                                 for which the procedure laid down in Article 2 thereof has been followed; furthermore, a Member State may also extend this
                                 period to 10 years by a single decision covering all the products marketed on its territory where it considers this necessary
                                 in the interest of public health. Member States are at liberty not to apply the abovementioned six-year period beyond the
                                 date of expiry of a patent protecting the original product.
                              
                              
                           
                     
               
         
         
         
            
            
               
                  
                  
                     
                        
                        
                           However, where the medicinal product is intended for a different therapeutic use from that of the other medicinal products
                                 marketed or is to be administered by different routes or in different doses, the results of appropriate pharmacological and
                                 toxicological texts and/or of appropriate clinical trials must be provided.
                              
                              
                           
                     
               
         
         
         
         
         
            
               (b)
                  ...’
               
         
         
         
         
         
         
         5
            
          The procedures established by Article 4.8(a)(i), (ii) and (iii) of Directive 65/65, as amended, are commonly known as ‘abridged
         procedures’. The specific procedure for obtaining marketing authorisation laid down by the last subparagraph of Article 4.8(a)
         (‘the proviso’) is known as the ‘hybrid’ abridged procedure.
         
         
         
         6
            
          The United Kingdom has exercised the option conferred on Member States by Article 4.8(a)(iii) of Directive 65/65, as amended,
         to extend the period referred to therein to 10 years.
         
         
         
         7
            
          Lastly, Article 5 of Directive 65/65, as amended, provides:
         ‘The authorisation provided for in Article 3 shall be refused if, after verification of the particulars and documents listed
         in Article 4, it proves that the medicinal product is harmful in the normal conditions of use, or that its therapeutic efficacy
         is lacking or is insufficiently substantiated by the applicant, or that its qualitative and quantitative composition is not
         as declared.
          Authorisation shall likewise be refused if the particulars and documents submitted in support of the application do not comply
         with Article 4.’
         
         The dispute in the main proceedings and the questions referred for a preliminary ruling
         
         8
            
          Sandimmun, Neoral, SangCya and Acceptine are all immuno-suppressants containing the active ingredient cyclosporin. Sandimmun
         and Neoral are produced by Novartis. SangCya and Acceptine, which may be regarded as identical for the purposes of the present
         proceedings and are hereinafter referred to collectively as ‘SangCya’, are produced by SangStat UK Ltd and Imtix-SangStat
         UK Ltd (hereinafter, collectively, ‘SangStat’).
         
         
         
         9
            
          Cyclosporin is primarily used to prevent rejection of organs or tissues in transplantation surgery. It is also used in the
         treatment of autoimmune diseases, including severe psoriasis, severe active rheumatoid arthritis, severe nephrotic syndrome
         and eczema.
         
         
         
         10
            
          Sandimmun, Neoral and SangCya are administered to patients orally. They are presented in their final form as a solution, and
         are taken by the patient in a drink. There are, however, differences between the products. They react differently when diluted
         for administration to the patient. Sandimmun forms a macroemulsion in an aqueous solution, whilst Neoral forms a microemulsion
         and SangCya undergoes a process of nanodispersion. That, in turn, has an effect on their bioavailability, that is, the rate
         and extent of their absorption into the body and of their transfer to the site of action. 
         
         
         
         11
            
          Bioavailability is important because cyclosporin has a narrow therapeutic index (the dose range within which clinical efficacy
         is observed with an acceptable safety profile). If the blood levels of cyclosporin in a transplant patient are too low, the
         risk of acute and chronic organ rejection increases. Conversely, if the levels are too high there is the risk of deteriorating
         kidney function and the patient’s immune system may be suppressed and the patient prone to the development of opportunistic
         infections and possibly lymphoma. For each of the products, after an initial dose at recommended levels has been given, the
         actual level of cyclosporin in the blood is monitored in individual patients and the maintenance dosage to be administered
         to the individual on a long-term basis may be adjusted accordingly to ensure that the level remains within the therapeutic
         index.
         
         
         
         12
            
          Sandimmun was the first cyclosporin product to be authorised within the Community. It was approved in 1983 following the submission
         by Sandoz Pharmaceuticals (UK) Ltd, now Novartis, of the full file of information required under Directive 65/65, as amended.
         Consequently, more than 10 years have elapsed since the first marketing authorisation for Sandimmun in the Community, and
         the 10-year period of data protection afforded to Novartis under the directive has expired. Patent protection in respect of
         Sandimmun has also expired.
         
         
         
         13
            
          Novartis embarked on a research and development programme with a view to producing a more powerful cyclosporin-based product
         than Sandimmun which would overcome Sandimmun’s problems of absorption and administration.
         
         
         
         14
            
          Novartis therefore developed the product called Neoral and obtained a patent for the cyclosporin formulation in that product.
         Neoral first received marketing authorisation within the European Union in Germany on 3 May 1994. Marketing authorisation
         in the United Kingdom was granted on 29 March 1995. The application made to the Medicines Control Agency (‘MCA’) as a ‘hybrid’
         abridged application cross-referred, with the consent of the person responsible, to the data relating to Sandimmun, under
         Article 4.8(a)(i) of Directive 65/65, as amended. However, it also included, under the proviso, data from further studies
         and clinical trials, in recognition of the fact that Neoral differed in some respects from the reference product. The approved
         indications for Neoral include all those approved for Sandimmun. In addition, as from January 1997 Neoral has been authorised
         for the treatment of steroid-dependent or steroid-resistant nephrotic syndrome in adults and children. Sandimmun and Neoral
         are both available on the market in the United Kingdom, but the former product represents only a small percentage of the total
         cyclosporin market, as compared with Neoral.
         
         
         
         15
            
          Neoral is absorbed into the bloodstream of patients more quickly and consistently than Sandimmun. The influence of concomitant
         food intake and other variable factors is significantly reduced in Neoral as compared with Sandimmun. Tests have shown that
         Neoral has approximately 29% higher bioavailability than Sandimmun.
         
         
         
         16
            
          On 27 January 1999, the MCA granted two marketing authorisations to SangStat in respect of SangCya by the hybrid abridged
         procedure under Article 4.8(a)(iii) of Directive 65/65, as amended. The reference product was Sandimmun, which, unlike Neoral,
         had been authorised in the Community for more than 10 years.
         
         
         
         17
            
          SangCya, which was not developed as a copy of Sandimmun or Neoral, is not identical to the latter. It is covered by patent
         applications and patents granted in the United States of America.
         
         
         
         18
            
          SangStat included with its application data to demonstrate the suprabioavailability of SangCya by comparison with Sandimmun
         and the essential similarity of those products. Studies showing bioequivalence between SangCya and Neoral sold in the United
         States were also included with the application.
         
         
         
         19
            
          For the purposes of granting marketing authorisations for SangCya the MCA also relied on data submitted by Novartis in support
         of its Neoral application.
         
         
         
         20
            
          The national proceedings concern the marketing authorisations granted to SangStat by the MCA in respect of SangCya on 27 January
         1999. Novartis applied for judicial review of the decision of the MCA to grant those marketing authorisations, but its application
         was dismissed.
         
         
         
         21
            
          Novartis lodged an appeal before the Court of Appeal seeking to have the contested marketing authorisations set aside. In
         support of its appeal Novartis submitted that the MCA had:
         
         (a)
            cross-referred unlawfully to the Neoral file (the cross-reference issue);
         
         
         (b)
            erred in finding that SangCya was essentially similar to Sandimmun, thereby exempting SangStat from the requirement to demonstrate
               that its product was safe notwithstanding its lack of bioequivalence with Sandimmun (the essential similarity issue);
            
         
         
         (c)
            infringed the principle of non-discrimination between Novartis and SangStat in terms of the authorisation procedure (the non-discrimination
               issue). 
            
         
         
         
         
         22
            
          The MCA contended that:
         
         (a)
            it was entitled to cross-refer to all information in its possession in assessing whether a product for which marketing authorisation
               was sought was safe;
            
         
         
         (b)
            questions of essential similarity were inherently questions of fact, degree and expert opinion for the competent national
               authorities, which enjoy a margin of discretion in deciding issues such as whether two products have the same pharmaceutical
               form. In any event, bioequivalence is not always required in order to demonstrate essential similarity;
            
         
         
         (c)
            there was no infringement of the principle of non-discrimination since Novartis and SangStat were not in the same position
               and, in any event, there was an objective and reasonable basis for distinguishing them.
            
         
         
         
         
         23
            
          In those circumstances the Court of Appeal (Civil Division) (England and Wales) decided to stay the proceedings and to seek
         a preliminary ruling from the Court of Justice on the following questions:
         
         ‘1.
            In considering a marketing authorisation for a new product (C) under Article 4.8(a)(iii) of Directive 65/65, referencing a
               product (A) authorised more than 6/10 years ago, is a national competent authority ever entitled to cross-refer, without consent,
               to data submitted in support of a product (B) which was authorised within the last 6/10 years?
            
         
         
         2.
            If so, may such cross-reference be made in circumstances where:
         
         
            
               (a)
                  product B was authorised under the Article 4.8(a) hybrid abridged procedure, referencing product A; and
               
         
         
         
            
               (b)
                  the data to which reference is made consists of clinical trials which the national competent authority indicated would be
                     necessary if the marketing authorisation was to be granted and which were submitted in order to demonstrate that product B,
                     though suprabioavailable to product A when administered in the same dose, is safe?
                  
               
         
         
          3.      (a)	Does the final subparagraph of Article 4.8(a) of Directive 65/65 (“the proviso”) apply only to applications made under
         Article 4.8(a)(iii) or to applications made under Article 4.8(a)(i) also?
                   (b)	Is essential similarity a prerequisite for the use of the proviso?
         
         4.
            Can products ever be essentially similar for the purposes of Article 4.8(a)(i) and (iii) of Directive 65/65 when they are
               not bioequivalent, and if so in what circumstances? 
            
         
         
         5.
            What is the meaning of the term pharmaceutical form, as used by the Court in its judgment in Case C-368/96 Generics? In particular, do two products have the same pharmaceutical form when they are administered to the patient in the form of
               a solution diluted to a macroemulsion, microemulsion and nanodispersion respectively?
            
         
         
         6.
            Is it consistent with the general principle of non-discrimination for a national competent authority, faced with hybrid applications
               for marketing authorisations under Article 4.8(a) of Directive 65/65 referencing product A for two products, neither of which
               is bioequivalent to product A:
            
         
         
            
               (i)
                  to indicate that it is necessary for a marketing authorisation to be granted for product B to be supported by full clinical
                     data of the type required by Part 4(F) of the Annex to Directive 75/318/EEC; but
                  
               
         
         
         
            
               (ii)
                  having considered the data filed in support of product B, to grant a marketing authorisation for product C if that application
                     is supported by trials not meeting the requirements of Part 4(F) of the Annex to Directive 75/318/EEC?’
                  
               
         
         
         
         Preliminary remarks
         
         24
            
          Pursuant to Article 4.8(a)(iii) of Directive 65/65, as amended, the applicant is not required to provide the results of pharmacological
         and toxicological tests or of clinical trials if it is demonstrated that the medicinal product is essentially similar to a
         product which has been authorised within the Community for at least six or 10 years and marketed in the Member State in respect
         of which the application is made. According to the final subparagraph of that provision, ‘where the medicinal product is intended
         for a different therapeutic use from that of the other medicinal products marketed or is to be administered by different routes
         or in different doses, the results of appropriate pharmacological and toxicological texts and/or of appropriate clinical trials
         must be provided’.
         
         
         
         25
            
          The dispute in the main proceedings concerns, inter alia, the question whether the MCA was entitled by that provision to exempt
         SangStat from providing such results by basing its decision on the results already provided by Novartis in the course of the
         procedures resulting in the grant to that company of marketing authorisations for Sandimmun and Neoral.
         
         
         
         26
            
          The following factors should be taken into account in relation to that question:
         
         
         
          
         –
            Neoral and SangCya are not bioequivalent since their bioavailability differs;
         
         
         
         
          
         –
            Neoral had been authorised for less than 10 years;
         
         
         
         
          
         –
            Neoral is a development of Sandimmun since Novartis obtained marketing authorisation for Neoral under the hybrid abridged
               procedure.
            
         
         
         
         
         
         27
            
          The questions referred for a preliminary ruling ask, more particularly, whether in such circumstances the dispensation from
         providing the pharmacological, toxicological and clinical documentation applies, as laid down by Article 4.8(a)(iii) of Directive
         65/65, as amended, in conjunction with the proviso, or whether the documentation provided by Novartis in the course of the
         marketing authorisation procedure for Neoral must be accorded a further period of protection of six or 10 years, so that it
         cannot be used by SangStat in assessing the application for marketing authorisation for SangCya.
         
         
         
         28
            
          In Case C-368/96 Generics and Others [1998] ECR I-7967, the Court interpreted Article 4.8(a)(iii) of Directive 65/65, as amended, ruling inter alia that:
         
         
         
          
         –
            the procedure established by that provision enables a second applicant for marketing authorisation for a given product to
               save the time and expense necessary in order to gather the pharmacological, toxicological and clinical data. In accordance
               with the fourth recital in the preamble to Directive 87/21, it also avoids, on public policy grounds, the repetition of tests
               on humans or animals where not absolutely necessary (Generics, paragraph 4);
            
         
         
         
         
          
         –
            under the abridged procedure, the obligation to carry out pharmacological, toxicological and clinical tests is replaced by
               an obligation to show that the medicinal product is so similar to a product which has been authorised for not less than six
               or 10 years in the Community and is marketed in the Member State for which the application is made that it does not differ
               significantly from that product as regards safety and efficacy, and that it is therefore essentially similar to the product
               already authorised (Generics, paragraph 24); 
            
         
         
         
         
          
         –
            a medicinal product is essentially similar, within the meaning of Article 4.8(a)(iii) of Directive 65/65, as amended, to an
               original medicinal product where it satisfies the criteria of having the same qualitative and quantitative composition in
               terms of active principles, of having the same pharmaceutical form and of being bioequivalent, unless it is apparent in the
               light of scientific knowledge that it differs significantly from the original product as regards safety or efficacy (Generics, paragraph 36);
            
         
         
         
         
          
         –
            a medicinal product that is essentially similar to a product which has been authorised for not less than six or 10 years and
               is marketed in the Member State for which the application is made may be authorised, under the abridged procedure, for all
               therapeutic indications already authorised for that product, even if those indications have been authorised for less than
               six or 10 years (Generics, paragraph 53). The Court stated in this connection that it is, where appropriate, for the Community legislature to adopt
               measures to reinforce the rules for the protection of innovating undertakings in the harmonised area with which the case is
               concerned (Generics, paragraph 52).
            
         
         
         
         
         
         29
            
          It should be added that the Court of Appeal rightly points out in the order for reference that the competent authority of
         a Member State in making a decision on an application for marketing authorisation must examine the safety and efficacy of
         the medicinal product, and that it is therefore permissible for that authority to take account of all data in its possession,
         from whatever source, to the extent that such data demonstrate that the product is harmful or that it lacks efficacy.
         
         
         
         30
            
          As stated in the first recital in the preamble to Directive 65/65, as amended, the primary purpose of any rules concerning
         the production and distribution of medicinal products must be to safeguard public health.
         
         
         
         31
            
          Accordingly, and pursuant to the first subparagraph of Article 5 of Directive 65/65, as amended, an application for marketing
         authorisation must be refused, inter alia, where, on the basis of data in the possession of the competent authority, it appears
         that a medicinal product is harmful or lacks efficacy. Clearly that authority is not precluded from basing its refusal on
         data submitted by other applicants, even if that data is protected within the meaning of Article 4.8(a)(iii) of Directive
         65/65, as amended.
         
         
         
         32
            
          Finally, the Court considers it appropriate to reply, first, to the fourth and fifth questions; second, to the third question;
         third, to the first and second questions and, lastly, to the sixth question.
         
         The fourth and fifth questionsThe fourth question
         
         33
            
          Pursuant to Article 4.8(a)(iii) of Directive 65/65, as amended, as interpreted by the Court, a medicinal product cannot be
         regarded as essentially similar to an original medicinal product if it does not satisfy the criteria of having the same qualitative
         and quantitative composition in terms of active principles, of having the same pharmaceutical form and of being bioequivalent
         (see Generics, paragraphs 36 and 37).
         
         
         
         34
            
          The same applies in respect of Article 4.8(a)(i) of Directive 65/65, as amended. The two abridged procedures in question are
         only distinguishable by the fact that the right to refer to the pharmacological, toxicological or clinical documentation contained
         in the file on the reference medicinal product is dependent, in the first case, on the consent of the person responsible for
         the marketing of that medicinal product and, in the second case, on the elapse of six or 10 years from the date on which the
         medicinal product was authorised in the Community.
         
         
         
         35
            
          Consequently, the reply to the fourth question must be that products cannot be regarded as essentially similar for the purposes
         of the application of Article 4.8(a)(i) or (iii) of Directive 65/65, as amended, where they are not bioequivalent.
         
         The fifth question
         
         36
            
          Neither Directive 65/65, as amended, nor, more generally, the Community legislation on medicinal products in force at the
         time of the facts in the main proceedings, defines the concept of pharmaceutical form.
         
         
         
         37
            
          According to the list of reference terms of the European Pharmacopoeia, drawn up under the auspices of the Council of Europe,
         pharmaceutical form is defined as the combination of the form in which a pharmaceutical product is presented by the manufacturer
         and the form in which it is administered, including the physical form.
         
         
         
         38
            
          Pursuant to the annex to Commission Directive 91/507/EEC of 19 July 1991 modifying the Annex to Council Directive 75/318/EEC
         on the approximation of the laws of Member States relating to analytical, pharmacotoxicological and clinical standards and
         protocols in respect of the testing of medicinal products (OJ 1991 L 270, p. 32), applicants for marketing authorisation are
         required in several respects to prepare the documentation and information to be submitted pursuant to Article 4 of Directive
         65/65, as amended, in accordance with the requirements set out in the European Pharmacopoeia. In particular, in Part 2, Section
         E, point 1 of that annex, it is provided, inter alia, that the provisions of the monographs of the European Pharmacopoeia
         on pharmaceutical forms apply to the products defined therein.
         
         
         
         39
            
          In those circumstances, the list of reference terms of the European Pharmacopoeia is capable of providing useful guidelines
         for the purpose of defining the concept of the pharmaceutical form of a medicinal product in order to address the question
         whether the medicinal products in question are essentially similar.
         
         
         
         40
            
          Consequently, for that purpose, account must be taken of the form in which the pharmaceutical product is presented by the
         manufacturer and the form in which it is administered, including the physical form.
         
         
         
         41
            
          Sandimmun, Neoral and SangCya are presented in the form of a solution to be mixed in a drink for administration to the patient.
         The fact that, when mixed, these three products form, respectively, a macroemulsion, a microemulsion and a nanodispersion,
         may provide information as to the form of administration but does not preclude their being treated as having the same pharmaceutical
         form for the purposes of addressing the question whether they are essentially similar within the meaning of Article 4.8(a)(i)
         or (iii) of Directive 65/65, as amended, provided that, as the United Kingdom Government and the Commission essentially submit,
         the differences in the form of administration are not significant in scientific terms.
         
         
         
         42
            
          The reply to the fifth question must therefore be that, for the purposes of the procedure laid down by Article 4.8(a)(i) and
         (iii) of Directive 65/65, as amended, in determining the pharmaceutical form of a medicinal product, account must be taken
         of the form in which it is presented and the form in which it is administered, including the physical form. In that context,
         medicinal products such as those at issue in the main proceedings, which are presented in the form of a solution to be mixed
         in a drink for administration to the patient and which, after mixing, form, respectively, a macroemulsion, a microemulsion
         and a nanodispersion, are to be treated as having the same pharmaceutical form, provided that the differences in the form
         of administration are not significant in scientific terms.
         
         The third questionThe first part of the third question
         
         43
            
          SangStat and Novartis, and the French and United Kingdom Governments, submit that the proviso applies not only to applications
         made under Article 4.8(a)(iii) but also to those made under Article 4.8(a)(i).
         
         
         
         44
            
          That argument must be upheld.
         
         
         
         45
            
          It does not appear that the difference between those two abridged procedures, as identified at paragraph 34 of the present
         judgment, is such as to justify restricting the hybrid abridged procedure provided for under the proviso to the situation
         covered by Article 4.8(a)(iii) of Directive 65/65, as amended.
         
         
         
         46
            
          It should be noted in this connection that, according to the fourth recital in the preamble to Directive 87/21, there are
         reasons of public policy for not repeating tests on humans or animals without imperative need. If it is ethically and scientifically
         inappropriate to repeat all tests for an application which otherwise satisfies all the requirements under Article 4.8(a)(iii)
         of Directive 65/65, as amended, it is also inappropriate to repeat those tests for an application which otherwise satisfies
         the requirements set out in Article 4.8(a)(i).
         
         
         
         47
            
          Consequently, the reply to the first part of the third question must be that the proviso, that is, the hybrid abridged procedure
         laid down by the final subparagraph of Article 4.8(a) of Directive 65/65, as amended, applies to applications for marketing
         authorisation based on Article 4.8(a)(i) or (iii).
         
         The second part of the third question
         
         48
            
          SangStat, the Danish and United Kingdom Governments and the Commission submit that recourse to the proviso is not restricted
         to cases in which the medicinal product in respect of which marketing authorisation is sought is essentially similar to an
         authorised product.
         
         
         
         49
            
          It should be noted in this regard that according to the express wording of Article 4.8(a)(iii) of Directive 65/65, as amended,
         relating to the abridged procedure, read in conjunction with the proviso, the essential similarity between the medicinal product
         in respect of which marketing authorisation is sought and the reference medicinal product is, as the Commission submits, the
         trigger for the application of the proviso.
         
         
         
         50
            
          Thus, the situation covered by the proviso, in which the new medicinal product differs from the reference medicinal product
         only in terms of its therapeutic indications, covers essentially similar medicinal products, that is, medicinal products having
         the same qualitative and quantitative composition in terms of active principles and the same pharmaceutical form and which
         are bioequivalent (Generics, paragraphs 36 and 42).
         
         
         
         51
            
          By contrast, as SangStat, the Danish and United Kingdom Governments and the Commission stated, the same does not apply in
         respect of a medicinal product which is to be administered by routes or in doses different from those of the reference medicinal
         product, since the former generally does not have the same bioavailability as the latter and is not therefore bioequivalent
         to the reference medicinal product.
         
         
         
         52
            
          Accordingly, if recourse to the proviso were only possible where the medicinal product in question is essentially similar
         to the reference medicinal product and therefore, inter alia, bioequivalent to that product, the proviso would be largely
         ineffective in the case of medicinal products to be administered by routes or in doses different from those of other medicinal
         products on the market.
         
         
         
         53
            
          Moreover, in the Notice to Applicants for marketing authorisation for medicinal products for human use in the Member States
         of the European Community, published by the Commission in 1993, it was expressly stated that the proviso could be applied
         where the new medicinal product did not satisfy the strict criteria for essential similarity when compared with the reference
         medicinal product.
         
         
         
         54
            
          Where the new medicinal product must be administered by routes or in doses different from those of the reference medicinal
         product, the purpose of the applicant’s obligation under the proviso to provide the results of appropriate pharmacological
         and toxicological tests and clinical trials is to prove the safety and efficacy of that medicinal product (see, to that effect,
         Generics, paragraph 23).
         
         
         
         55
            
          In the light of the foregoing, the reply to the second part of the third question must be that an application for marketing
         authorisation for a medicinal product may be made under the proviso with reference to an authorised medicinal product provided
         that the medicinal product in respect of which marketing authorisation is sought is essentially similar to the authorised
         medicinal product, unless one or more of the differences set out in the proviso apply, as the case may be.
         
         The first and second questions
         
         56
            
          By these two questions, which should be read together, the referring court asks essentially whether, in considering an application
         for marketing authorisation for a new product C under Article 4.8(a)(iii) of Directive 65/65, as amended, with reference to
         a product A authorised for more than six or 10 years, the competent authority of a Member State is entitled, with a view to
         granting marketing authorisation, to refer, without the consent of the person responsible for marketing, to data submitted
         in support of a product B which was authorised within the previous six or 10 years under the hybrid abridged procedure of
         Article 4.8(a) of Directive 65/65, as amended, with reference to product A, where those data consist of clinical trials provided
         in order to demonstrate that product B, though suprabioavailable to product A when administered in the same dose, is safe.
         
         
         
         57
            
          It should be noted that an applicant for marketing authorisation for a medicinal product essentially similar to a product
         authorised for at least six or 10 years in the Community and marketed in the Member State for which the application is made
         is not required, under Article 4.8(a)(iii) of Directive 65/65, as amended, to supply pharmacological, toxicological and clinical
         documentation for any of the therapeutic indications to which the documentation for the original medicinal product relates,
         including those authorised for less than six or 10 years (see, to that effect, Generics, paragraphs 43 and 44).
         
         
         
         58
            
          Thus, the pharmacological, toxicological and clinical documentation covering the new therapeutic indications of a medicinal
         product already authorised cannot be accorded a further period of protection of six or 10 years.
         
         
         
         59
            
          The same applies in respect of pharmacological, toxicological and clinical documentation provided for a medicinal product
         which is to be administered by routes or in doses different from those of other medicinal products on the market. 
         
         
         
         60
            
          In the light of the proviso, such a medicinal product is a development of the original or reference medicinal product in the
         same way as a medicinal product intended for a different therapeutic use from that of the original or reference medicinal
         product.
         
         
         
         61
            
          In that context, as stated at paragraph 51 of the present judgment, it is not decisive that a medicinal product to be administered
         by routes or in doses different from those of the reference medicinal product does not, unlike a medicinal product intended
         for a therapeutic use different from that of the reference medicinal product, generally satisfy all the criteria for essential
         similarity.
         
         
         
         62
            
          It should be noted in that connection that whether or not the product resulting from the development of the reference medicinal
         product satisfies all the criteria for essential similarity to the latter product does not necessarily bear any relationship
         to the cost or difficulty involved in that development.
         
         
         
         63
            
          Moreover, if the applicant for marketing authorisation for a medicinal product were only permitted to refer to the pharmacological,
         toxicological and clinical documentation relating to products resulting from the development of the reference medicinal product
         where all the criteria for essential similarity are met, it would largely be prevented from referring to that documentation
         where those products are to be administered by routes or in doses different from those of the reference medicinal product,
         whilst such reference is permitted where the product is intended for a therapeutic use different from that of the reference
         medicinal product.
         
         
         
         64
            
          Therefore, the applicant for marketing authorisation for a medicinal product may refer to that documentation where the products
         resulting from the development of the reference medicinal product and the reference medicinal product are essentially similar,
         apart from the route of administration or the dose, as the case may be.
         
         
         
         65
            
          If product B resulting from the development of the reference product A is essentially similar to that reference product, apart
         from its bioavailability, since that difference is nevertheless not attributable to a difference in the route of administration
         or the dose, the applicant for marketing authorisation for product C is entitled to refer to the clinical documentation in
         respect of product B.
         
         
         
         66
            
          If, as stated at paragraph 64 of the present judgment, the applicant for marketing authorisation for product C may refer to
         the pharmacological, toxicological and clinical documentation in respect of product B, which is the product of the development
         of the reference product A and essentially similar thereto, apart from the route of administration or the dose, as the case
         may be, since the differences in those two factors generally imply that products A and B are not bioequivalent (see paragraph
         51 of the present judgment), it must, a fortiori, be able to do so where products A and B are distinguishable only by their different bioavailability, even though the route
         of administration and dose remain unchanged.
         
         
         
         67
            
          It follows that, in considering an application for marketing authorisation for a new product C under Article 4.8(a)(iii) of
         Directive 65/65, as amended, with reference to a product A authorised for more than six or 10 years, the competent authority
         of a Member State is entitled, with a view to granting marketing authorisation, to refer without the consent of the person
         responsible for marketing to data submitted in support of a product B which was authorised within the previous six or 10 years
         under the hybrid abridged procedure laid down by Article 4.8(a) of Directive 65/65, as amended, with reference to product
         A, where those data consist of clinical trials provided in order to demonstrate that product B, though suprabioavailable to
         product A when administered in the same dose, is safe.
         
         The sixth question
         
         68
            
          By this question, the Court of Appeal asks whether, in considering two hybrid applications for marketing authorisation for
         products B and C brought under the proviso and referring to product A, the competent authority of a Member State infringes
         the principle of non-discrimination if, as a precondition for the grant of marketing authorisation, it requires full clinical
         data on the bioavailability of product B, but, having examined the data filed in support of product B, does not require the
         same data for product C.
         
         
         
         69
            
          According to settled case-law, the principle of non-discrimination requires that comparable situations not be treated differently
         and different situations not be treated in the same way unless such treatment is objectively justified (see, inter alia, Case
         106/83 Sermide [1984] ECR 4209, paragraph 28, and Case C-137/00 Milk Marque and National Farmers’ Union [2003] ECR I-0000, paragraph 126).
         
         
         
         70
            
          The situation of the applicant for marketing authorisation for product B is, in any event, not comparable to that of the applicant
         for marketing authorisation for product C. When the latter applicant applies for marketing authorisation, product B is authorised
         and the authorities are assured of the safety and efficacy of that product.
         
         
         
         71
            
          That finding does not prejudge the question whether the competent authority of a Member State is entitled to base its decision
         on the data filed in support of product B when considering the application for marketing authorisation for product C.
         
         
         
         72
            
          Consequently, the reply to the sixth question must be that, in considering two hybrid applications for marketing authorisation
         for products B and C brought under the proviso and referring to product A, the competent authority of a Member State does
         not infringe the principle of non-discrimination where, as a precondition for the grant of marketing authorisation, it requires
         full clinical data on the bioavailability of product B, but, having examined the data filed in support of product B, does
         not require the same data for product C.
         
         
         Costs
         73
            
          The costs incurred by the United Kingdom, Danish, French, Netherlands and Portuguese Governments and by the Commission, which
         have submitted observations to the Court, are not recoverable. Since these proceedings are, for the parties to the main proceedings,
         a step in the action pending before the national court, the decision on costs is a matter for that court. 
         
         
         On those grounds,
         
         
         
            
            THE COURT (Sixth Chamber),
         
         
          in answer to the questions referred to it by the Court of Appeal (Civil Division) (England and Wales) by order of 22 February
         2001, hereby rules:
         
            
            
             
               1.
                   Products cannot be regarded as essentially similar for the purposes of the application of Article 4.8(a)(i) or (iii) of Council
                     Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by law, regulation or administrative action
                     relating to medicinal products, as amended by Council Directives 87/21/EEC of 22 December 1986, 89/341/EEC of 3 May 1989,
                     and 93/39/EEC of 14 June 1993, where they are not bioequivalent.
                  
               
            
            
            
             
               2.
                  For the purposes of the procedure laid down by Article 4.8(a)(i) and (iii) of Directive 65/65, as amended, in determining
                     the pharmaceutical form of a medicinal product, account must be taken of the form in which it is presented and the form in
                     which it is administered, including the physical form. In that context, medicinal products such as those at issue in the main
                     proceedings, which are presented in the form of a solution to be mixed in a drink for administration to the patient and which,
                     after mixing, form, respectively, a macroemulsion, a microemulsion and a nanodispersion, are to be treated as having the same
                     pharmaceutical form, provided that the differences in the form of administration are not significant in scientific terms.
                  
               
            
            
            
             
               3.
                  The proviso, that is, the hybrid abridged procedure laid down by the final subparagraph of Article 4.8(a) of Directive 65/65,
                     as amended, applies to applications for marketing authorisation based on Article 4.8(a)(i) or (iii).
                  
               
            
            
                  An application for marketing authorisation for a medicinal product may be made under the proviso, that is, by the abridged
                           hybrid procedure provided for in the final subparagraph of Article 4.8(a) of Directive 65/65, as amended, with reference to
                           an authorised medicinal product provided that the medicinal product in respect of which marketing authorisation is sought
                           is essentially similar to the authorised medicinal product, unless one or more of the differences set out in the proviso apply,
                           as the case may be.
                     
                  
            
            
            
            
             
               4.
                  In considering an application for marketing authorisation for a new product C under Article 4.8(a)(iii) of Directive 65/65,
                     as amended, with reference to a product A authorised for more than six or 10 years, the competent authority of a Member State
                     is entitled, with a view to granting marketing authorisation, to refer without the consent of the person responsible for marketing
                     to data submitted in support of a product B which was authorised within the previous six or 10 years under the hybrid abridged
                     procedure laid down by Article 4.8(a) of Directive 65/65, as amended, with reference to product A, where those data consist
                     of clinical trials provided in order to demonstrate that product B, though suprabioavailable to product A when administered
                     in the same dose, is safe.
                  
               
            
            
            
             
               5.
                  In considering two hybrid applications for marketing authorisation for products B and C brought under the final subparagraph
                     of Article 4.8(a) of Directive 65/65, as amended, and referring to product A, the competent authority of a Member State does
                     not infringe the principle of non-discrimination where, as a precondition for the grant of marketing authorisation, it requires
                     full clinical data on the bioavailability of product B, but, having examined the data filed in support of product B, does
                     not require the same data for product C.
                  
               
            
            
                  Skouris
               
               
                  Gulmann
               
               
                  Cunha Rodrigues
               
            
                  Puissochet
               
               
                  
               
               
                  Schintgen
               
            
                  
               
               
                  
               
               
                  
               
            
                  
               
               
                  
               
               
                  
               
            
                  
               
               
                  
               
               
                  
               
            
            
            
            
            
            
            
            
         
         
          Delivered in open court in Luxembourg on 29 April 2004.
         
         
         
         
                  R. Grass
               
               
                  V. Skouris
               
            
         
         
         
                  Registrar
               
               
                  President
               
            
      
      
          1 –
            
            Language of the case: English.