CELEX: 62003CC0036
Language: en
Date: 2004-07-08
Title: Opinion of Mr Advocate General Jacobs delivered on 8 July 2004. # The Queen, on the application of Approved Prescription Services Ltd v Licensing Authority. # Reference for a preliminary ruling: High Court of Justice (England & Wales), Queen's Bench Division (Administrative Court) - United Kingdom. # Medicinal products - Marketing authorisation - Procedures for essentially similar products. # Case C-36/03.

OPINION OF ADVOCATE GENERAL
      JACOBS
      delivered on 8 July 2004 (1)
      
      Case C-36/03
      Approved Prescription Services Ltd
      v
      Licensing Authority (acting by the Medicines Control Agency)
      1.        This reference from the High Court of England and Wales (Queen’s Bench Division) concerns an application for national marketing
         authorisation for a medicinal product pursuant to 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, (hereinafter, ‘the Directive’), (2) as it stood prior to its recent amendment. (3)
      
      2.        Ordinarily, the Directive requires an applicant to supply a full set of data in order to show the safety and efficacy of its
         product.  However, in derogation from that full procedure, the Directive also specifies various abridged procedures, whereby
         the applicant is relieved of the obligation to supply certain data, and may refer instead to data submitted in respect of
         another previously authorised product.  Under one such procedure, as it operated at the material time, the applicant could
         make such reference where its product was essentially similar to the other product, and where the other product had been authorised
         for a stipulated period (fixed, for the purposes of the present case, at 10 years).  Under another such procedure, the applicant
         could refer in part to the data submitted in respect of another product but could also submit additional ‘bridging’ data to
         deal with certain specified types of difference between the two otherwise similar products. 
      
      3.        The present case concerns fluoxetine liquid, the generic name for an anti-depressant which is the active ingredient of products
         marketed under the name of Prozac.  Marketing authorisation for Prozac capsules was first obtained in 1988, and authorisation
         for Prozac liquid (which was granted on the basis of bridging data supplementing the data already provided for the capsules)
         in 1992.  In 1999, less than 10 years after the authorisation of Prozac liquid, a generic manufacturer applied for authorisation
         to market generic fluoxetine liquid, relying on the data supplied for the previous authorisation.  The application was refused
         on the grounds that Prozac liquid had been authorised for less than 10 years, and that fluoxetine liquid was not essentially
         similar to Prozac capsules. 
      
      4.        In the context of an application for judicial review of that refusal, the referring court wishes to know whether, under the
         relevant provisions, the applicant for a marketing authorisation for a new medicinal product (hereinafter, ‘the new product’
         or ‘product C’) may rely upon data submitted in respect of an essentially similar product (hereinafter, ‘the variant’ or ‘product
         B’) which has been authorised within the Community for less than the stipulated period, but which is a version of a product
         (hereinafter, ‘the original product’ or ‘product A’) which has been authorised for at least that period, despite the fact
         that products A and B have a different pharmaceutical form or are otherwise lacking in essential similarity. 
      
      5.        The Court has considered the interpretation of the Directive on several occasions, and the question referred falls to be determined
         in the light of its judgments in Generics (4) and Novartis. (5)  Since the material time, the Directive has been revised in such a way as to give, for the future, a clear affirmative answer
         to the question raised in the present proceedings. 
      
        
       Legal framework 
       Community legislation 
      6.        The Directive consolidates in one text a number of directives dealing with medicinal products and codifies amendments made
         to those directives.  Chapter 1 of Title III of the Directive is made up of Articles 6 to 12, and deals with marketing authorisation
         for medicinal products. (6)  Since the material time, the Directive has been amended on several occasions.  Of relevance to the issue raised by the present
         proceedings are the amendments effected by Directive 2004/27/EC, which are set out below. (7)
      
      7.        Article 6(1) provides that a medicinal product may be placed on the market in a Member State only if a marketing authorisation
         has been issued by the competent authorities of that Member State. 
      
      8.        Articles 8 and 10 provide for several possible procedures for obtaining a national marketing authorisation.  Article 8(3)
         identifies the particulars and documents which must be supplied in support of an application under what might be termed the
         full procedure.  It provides that such information must be ‘submitted in accordance with Annex I’ of the Directive.  Pursuant
         to Article 8(3)(i), (8) the applicant must ordinarily provide the results of: 
      
      ‘–      physico-chemical, biological or microbiological tests 
      –        pharmacological and toxicological tests; 
      –        clinical trials.’ 
      9.        Article 10 lays down various procedures alternative to the full procedure, whereby, in certain specified circumstances, an
         applicant may be relieved of the obligation to provide some or all of the results of pharmacological and toxicological tests
         and of clinical trials normally required by Article 8(3)(i), and may rely instead on data submitted in respect of another
         ‘reference’ product which has already been authorised.  The obligation to provide full particulars of the physico-chemical
         nature of the product is not affected. 
      
      10.      At the material time, Article 10(1)(a) provided for the so-called ‘abridged’ procedure, which relieved the applicant of the
         obligation to supply any of the relevant types of data, if it could demonstrate: 
      
      ‘… 
      (i)      either that the medicinal product is essentially similar to a medicinal product authorised in the Member State concerned by
         the application and that the holder of the marketing authorisation for the original medicinal product has consented to the
         toxicological, pharmacological and/or clinical references contained in the file on the original medicinal product being used
         for the purpose of examining the application in question; 
      
      … 
      (iii) or that the medicinal product is essentially similar to a medicinal product which has been authorised within the Community,
         in accordance with Community provisions in force, for not less than 6 years and is marketed in the Member State for which
         the application is made … [A] Member State may … extend this period to 10 years by a single Decision covering all the medicinal
         products marketed on its territory where it considers this necessary in the interest of public health …’ 
      
      11.      At the material time, a further procedure, commonly referred to as the ‘hybrid abridged’ procedure, was laid down in the final
         paragraph of Article 10(1)(a), a provision commonly known as the proviso: 
      
      ‘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 toxicological and
         pharmacological tests and/or of appropriate clinical trials must be provided.’ 
      
      12.      Under the proviso, an applicant was therefore required to provide only the results of such pharmacological or toxicological
         tests and clinical trials as were appropriate in the light of the difference in therapeutic use, route of administration,
         or dose from the other medicinal products marketed.  Otherwise, the applicant relied upon the data relating to the reference
         product which it was required to specify under Article 10(1)(a)(i) or (iii).  The additional data which the applicant was
         required to supply under the proviso were commonly known as ‘bridging data’. 
      
      13.      The objectives underlying the various procedures for obtaining a marketing authorisation are apparent from the preamble to
         the Directive.  The second recital makes clear that the essential aim of any rules governing the production, distribution
         and use of medicinal products must be to safeguard public health.  As appears from the 9th and 10th recitals, the procedures
         specified in Article 10(1)(a) are also aimed at ensuring that innovative firms are not placed at a disadvantage and at avoiding
         repetitive tests on humans or animals without over-riding cause. 
      
        
       The Notice to Applicants 
      14.      As set out above, Article 8(3) of the Directive requires that the particulars and documents in support of an application for
         marketing authorisation must be ‘submitted in accordance with Annex I’.
      
      15.      The first paragraph in the introduction to that Annex requires the particulars and documents accompanying an application for
         marketing authorisation to be prepared in a manner which takes account of the guidance published by the Commission in a document
         which at the material time was entitled ‘The rules governing medicinal products in the European Community, Volume II:  Notice
         to applicants for marketing authorisations for medicinal products for human use in the Member States of the European Community’. (9)  Volume II is generally known and is hereinafter referred to as the Notice to Applicants. (10)
      
      16.      As its foreword explains, the Notice to Applicants ‘has been prepared by the European Commission, in consultation with the
         competent authorities of the Member States and the European Agency for the Evaluation of Medicinal Products’.  It therefore
         presents the ‘harmonised views’ of the Member States and the Agency on how the ‘legal requirements of the Directives and the
         Regulations … may be met’.  At the same time, the foreword states that the Notice ‘has no legal force and does not necessarily
         represent the final views of the Commission’.  In case of doubt, therefore, reference should be made to the appropriate Community
         legislation. 
      
      17.      Volume 2A of the Notice to Applicants concerns procedures for marketing authorisation.  Section 4.2 of chapter 1 thereof deals
         with applications under the abridged procedure.  It states that: 
      
      ‘The dossier of a new strength, new pharmaceutical form, new indication (called deliberately “line extensions” see section
         5.2) of an existing medicinal product from the same marketing authorisation holder based on a complete dossier is also considered
         as a complete dossier.  An essentially similar product (informed consent or generic) can refer to the dossier of the line
         extension of the original medicinal product.  Therefore, a line extension for a generic medicinal product can be applied for
         by reference to the line extension of the original medicinal product.’
      
      18.      Section 4.2 also supplies the following definitions: 
      ‘Essential similarity: the product applied for under the abridged procedure must be essentially similar to the original/reference
         medicinal product.  In this context the following definitions are applicable. 
      
      An original medicinal product is a medicinal product that has been authorised within the Community for not less than 6 or 10 years.  The marketing authorisation
         of this medicinal product is based on a complete dossier. 
      
      A reference medicinal product is a version of the original medicinal product which is marketed in the Member State for which the application is made and
         which is used to claim essential similarity.  In this Member State the reference medicinal product can be authorised for less
         than 6 or 10 years.  This reference medicinal product might be of another strength or pharmaceutical form or be approved for
         other indications or have other excipients than the original medicinal product.  
      
      A medicinal product used as comparison for bioequivalence study, where a bioequivalence study is applicable, is a version of the original medicinal product that is authorised within the
         Community.  This medicinal product is normally the same as the reference medicinal product.’
      
        
       Community case-law 
      19.      The Court of Justice has on several occasions considered the provisions which were at the time to which the present proceedings
         relate contained in Article 10(1)(a), most notably in the Generics and Novartis cases. (11)  Those cases have shed light upon the meaning of essential similarity; the operation of the hybrid abridged procedure laid
         down in the proviso; and the circumstances in which an applicant under Article 10(1)(a)(iii) may claim essential similarity
         with, and rely upon data submitted in respect of, a later version of the reference product, which later version was authorised
         less than 6 or 10 years previously. 
      
        
       The meaning of essential similarity 
      20.      The Court held in Generics, (12) and confirmed in Novartis, (13) that one medicinal product is essentially similar to another ‘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’. 
      
      21.      As to the meaning of pharmaceutical form for the purpose of that test, the Court held in Novartis that, in determining the pharmaceutical form of a given 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’. (14)
      
        
       The hybrid abridged procedure 
      22.      As with the abridged procedure, the proviso clearly permits some reliance upon data previously submitted in respect of a reference
         product, but requires additional bridging data on account of a difference in therapeutic use, route of administration or dose
         between the reference product and the new product to which the application relates.  
      
      23.      In Novartis, the Court held that the proviso may be used in conjunction with either Article 10(1)(a)(i) (where the reference product
         has been authorised in the country concerned by the application, and where the consent of the person responsible for marketing
         the reference product has been obtained) or Article 10(1)(a)(iii) (where the reference product has been authorised within
         the Community for not less than 6 or 10 years and is marketed in the Member State for which the application is made). (15)
      
      24.      The Court also held that under the hybrid abridged procedure, by contrast with the abridged procedure, the product for which
         authorisation is sought need not in all cases be essentially similar to the reference product. 
      
      25.      The Court noted that if essential similarity were required, 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, given that
         the former are generally not bioequivalent to the latter. (16)
      
      26.      The Court therefore held that an application for marketing authorisation may be made under the proviso with reference to an
         authorised medicinal product provided that the product in respect of which authorisation is sought is essentially similar
         to the authorised medicinal product, unless one or more of the differences set out in the proviso apply. (17)
      
        
       The permissibility of reference to data submitted in respect of a variant of the original product 
      27.      In Generics, the Court held that under Article 10(1)(a)(iii), a new medicinal product which is essentially similar to another product
         which has been authorised for not less than 6 or 10 years in the Community and is marketed in the Member State for which the
         application is made may be authorised for all therapeutic indications, dosage forms, doses and dosage schedules already authorised
         for the reference product, including those authorised for less than 6 or 10 years. (18)
      
      28.      The Generics judgment thus made clear that an applicant may in certain circumstances rely not only upon the data submitted to obtain the
         first authorisation of a reference product, not less than 6 or 10 years previously, but also data submitted subsequently,
         to obtain the further authorisation of some variant upon the reference product, even where the latter was filed within the
         last 6 or 10 years. 
      
      29.      The Generics judgment gave rise to varying interpretations.  According to one interpretation, it was necessary for an applicant to show
         not only that its product was essentially similar to the variant product, but also that the original product and its variant
         were themselves essentially similar to one another. 
      
      30.      The problem with such an interpretation was that, given the definition of essential similarity adopted by the Court, several
         of the types of variation specified in Generics would unavoidably result in the original product and its variant lacking essential similarity to one another. 
      
      31.      The preponderance of opinion among the national and Community regulators, as reflected in the Notice to Applicants, was that
         the Generics judgment must be interpreted as permitting reference, by the applicant for an authorisation of a new product under Article
         10(1)(a)(iii), to data submitted in respect of a variant of the original product in the circumstances identified in that judgment
         even if the variant lacks essential similarity to the original product, provided that the new product is essentially similar
         to the variant. 
      
      32.      In Novartis, the Court was able to elaborate upon its interpretation of Article 10(1)(a)(iii) in Generics. 
      
      33.      First, the Court made clear that essential similarity is not always necessary as between the original product and its variant
         in order for reference to be made to data submitted in respect of the variant.  Otherwise, the circumstances in which such
         reference could be made would effectively be limited to new therapeutic indications, given the likely impact of other types
         of change upon bioavailability, one of the criteria of essential similarity. (19)
      
      34.      Secondly, the Court revisited the types of variation between the original product and its variant which would permit reference
         to the variant’s data.  
      
      35.      It held that an applicant may rely on such data whenever the original product and its variant differ in one of the respects
         identified in the proviso, namely in their therapeutic indication, route of administration or dose. (20)  The Court explained that: 
      
      ‘In the light of the proviso, [the variant product] is a development of the original or reference product in the same way
         as a medicinal product intended for a different therapeutic use from that of the original or reference medicinal product.’ (21)
      
      36.      The Court made clear that the criteria explicitly specified in the proviso are not, however, exhaustive of the respects in
         which the variant product may exceed the parameters of essential similarity with the original product without thereby obtaining
         an additional period of data exclusivity. 
      
      37.      Specifically, the Court held that where Products A and B are essentially similar but for their differing bioavailability,
         an applicant for marketing authorisation for Product C may none the less rely upon the data submitted in respect of Product
         B. (22)  The Court reasoned as follows: 
      
      ‘If … the applicant for marketing authorisation for product C may refer to the … documentation in respect of product B, which
         is … essentially similar [to product A], apart from the route of administration or the dose, … since the differences in those
         two factors generally imply that products A and B are not bioequivalent … 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.’ (23)
      
        
       Subsequent amendments to the Directive 
      38.      Although enacted after the material time, it is useful to consider several amendments to the Directive effected by Directive
         2004/27/EC. (24)  Article 1(5) thereof adds the following subparagraph to Article 6(1) of the Directive:
      
      ‘When a medicinal product has been granted an initial marketing authorisation in accordance with the first subparagraph, any
         additional strengths, pharmaceutical forms, administrative routes, presentations, as well as any variations and extensions
         shall also be granted an authorisation in accordance with the first subparagraph and shall be included in the initial marketing
         authorisation.  All these marketing authorisations shall be considered as belonging to the same global marketing authorisation,
         in particular for the purpose of the application of Article 10(1).’ 
      
      39.      Article 1(8) of Directive 2004/27/EC replaces the previous text of Article 10 with a new set of provisions.  A revised version
         of the abridged procedure previously laid down in Article 10(1)(a)(iii) is now contained in Article 10(1).  The concept of
         essential similarity has been replaced by a requirement upon applicants to show that their product is a generic of a reference
         medicinal product which has been authorised for not less than eight years. 
      
      40.      A generic medicinal product is defined by Article 10(2)(b) to mean ‘a medicinal product which has the same qualitative and
         quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose
         bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies’. 
      
      41.      Article 10(3) of the Directive provides for a variant on the hybrid abridged procedure.  It states that: 
      ‘In cases where the medicinal product does not fall within the definition of a generic medicinal product as provided in paragraph
         2(b) or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active
         substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal
         product, the results of the appropriate pre-clinical tests or clinical trials shall be provided.’ 
      
      42.      It follows from those amendments that the Directive explicitly now permits the authorisation of a new product which is the
         generic of (i.e. essentially similar to) a variant of an original product which has been authorised for the requisite period
         and which differs from the original product in terms of its pharmaceutical form.  The data submitted in respect of the variant
         are to be regarded, pursuant to the second subparagraph of Article 6(1) of the Directive, as forming part of the initial marketing
         authorisation for the purposes of the application of Article 10(1) of the Directive.
      
        
       National law 
      43.      In the United Kingdom, the licensing authority established by the Medicines Act 1968 is designated as the competent authority
         for the purposes of the Directive.  It operates administratively through an executive agency of the Department of Health,
         which at the material time was the Medicines Control Agency (‘the MCA’).  The United Kingdom has exercised its option, pursuant
         to Article 10(1)(a)(iii), to extend the period specified in that provision from 6 to 10 years. 
      
        
       Facts 
      44.      In the present case, Approved Prescription Services Limited (‘APS’), a generic pharmaceutical manufacturer based in the United
         Kingdom, challenges a decision of the MCA refusing to permit its application for a marketing authorisation to proceed under
         the abridged procedure which was at that time laid down in Article 10(1)(a)(iii) of the Directive. 
      
      45.      In October 1999, APS applied to the MCA for a marketing authorisation for fluoxetine liquid 20mg/5ml, which is the generic
         name for an anti-depressive medication. 
      
      46.      APS sought to rely on the abridged procedure under Article 10(1)(a)(iii) on the basis that its product was essentially similar
         to Prozac liquid.  Prozac liquid is the proprietary name for a product made by the pharmaceuticals company, Eli Lilly, which
         contains fluoxetine as its active ingredient. 
      
      47.      In its application, APS specified the date of first marketing authorisation for its reference product as 25 November 1988. 
         That was the date on which Prozac capsules were authorised in the United Kingdom, the first product containing fluoxetine
         as its active ingredient to obtain such authorisation. 
      
      48.      Prozac liquid was first authorised within the Community on 14 October 1992, in Denmark.  It obtained authorisation in the
         United Kingdom on 28 October 1992, following an application by Eli Lilly under the hybrid abridged procedure based on what
         was later to become Article 10(1)(a)(i) and the proviso.  The reference product for that application was Prozac capsules. 
         Eli Lilly had accepted that Prozac liquid was not essentially similar to Prozac capsules, by reason of its different pharmaceutical
         form, and had provided bridging data to demonstrate that the products were bioequivalent. 
      
      49.      The MCA considered that APS could not rely upon Prozac liquid as a reference product for the purposes of Article 10(1)(a)(iii)
         because at the time of APS’ application, it had been authorised for less than 10 years.  APS was therefore required to amend
         its application so as to cite the reference product as Prozac capsules, the first fluoxetine product, which had been authorised
         for more than 10 years.  Because Prozac capsules are not essentially similar to fluoxetine liquid, APS would then need to
         proceed under the hybrid abridged procedure, and to submit bridging data in the form of a bioequivalence study comparing the
         two types of product. 
      
        
       National proceedings and questions referred 
      50.      APS has applied to the High Court for judicial review of the MCA’s decision refusing to permit its application for a marketing
         authorisation for fluoxetine liquid to proceed as an abridged application under Article 10(1)(a)(iii) of the Directive.  Citing
         the Court’s judgment in Generics and the Notice to Applicants, APS argued before the national court that it was entitled to rely upon the data submitted in
         respect of Prozac liquid. 
      
      51.      The High Court decided to suspend the proceedings before it and to refer the following question to the Court of Justice: 
      ‘Can an application for a marketing authorisation for a medicinal Product C validly be made under the first paragraph of Article
         10(1)(a)(iii) of Directive 2001/83/EC, where the application seeks to demonstrate that Product C is essentially similar to
         another product, Product B, in circumstances where: 
      
      (1)      product B is related to an original medicinal Product A, in that Product B has been authorised as a “line extension” of Product
         A, but has a different pharmaceutical form from Product A or is otherwise not “essentially similar” to Product A within the
         meaning of Article 10(1)(a)(iii);  and 
      
      (2)      product A has been authorised for marketing in the Community for more than the 6/10 year period stipulated in Article 10(1)(a)(iii); 
         and 
      
      (3)      product B has been authorised for marketing for less than the 6/10 year period stipulated in Article 10(1)(a)(iii).’ 
      52.      The reference made to the first paragraph of Article 10(1)(a)(iii) is presumably intended to make clear that the question
         relates only to the abridged procedure and not the hybrid abridged procedure laid down in the proviso.  It is now clear following
         the Court’s judgment in Novartis that the proviso did not form part of Article 10(1)(a)(iii) but rather applied to Article 10(1)(a) in its entirety. 
      
      53.      The Court has received written observations from APS, Eli Lilly, the Danish, French, Netherlands and United Kingdom Governments
         and from the Commission.  APS, the Danish and United Kingdom Governments, and the Commission made oral submissions at the
         hearing. 
      
        
       Assessment 
      54.      Following the hearing, three distinct positions are apparent from the observations before the Court. 
      55.      First, APS, the Commission, Denmark, France and the Netherlands submit that reference may be made in support of an application
         for the marketing authorisation of product C, made under the abridged procedure laid down by Article 10(1)(a)(iii), to the
         data filed in respect of an essentially similar product B, where product B is a new pharmaceutical form of product A, and
         where product A has been licensed for the requisite period of 6 to 10 years.  They therefore propose an affirmative response
         to the question referred. 
      
      56.      Secondly, in their written observations, which were submitted before the Court delivered its judgment in Novartis, (25) Eli Lilly and the United Kingdom Government argue, by contrast, that an applicant seeking authorisation to market product
         C under Article 10(1)(a)(iii) would need to show the essential similarity of that product to product A (the original product
         which had been licensed for at least the 6 or 10 year period), as well as product B (a variant or line extension of product
         A) in order to be able to rely on product B’s data.  Under that approach, the question referred would be answered in the negative.
         
      
      57.      Thirdly, at the hearing, the United Kingdom Government modified its position in the light of Novartis.  It accepted that reference could be made in support of product C’s application to product B’s data, despite a difference
         of pharmaceutical form between products A and B.  However, it submitted that the application in respect of product C would
         need to be made under the hybrid abridged procedure laid down in the proviso.  It therefore persisted in proposing a negative
         response to the question referred in the present proceedings, which is framed in terms of the abridged procedure provided
         for, at the material time, in Article 10(1)(a)(iii). 
      
      58.      It appears to me that the first position, which is adopted by APS, the Commission, Denmark, France and the Netherlands, is
         the correct one. 
      
      59.      It is now clear from the Court’s judgment in Novartis that reference may in certain circumstances be made to data submitted in respect of a variant of an original product, where
         the original product has been authorised for the stipulated period even though the variant has not been so authorised. (26)  The position taken by Eli Lilly and the United Kingdom in their written submissions can therefore no longer be sustained.
         
      
      60.      Two issues then remain to be considered.  The first is whether such reference could be made where the difference between products
         A and B relates to their pharmaceutical form.  The second is whether the application may proceed under Article 10(1)(a)(iii)
         as APS, the Commission, Denmark, France and the Netherlands contend, or whether it should instead be made under the proviso.
         
      
      61.      All of the parties except Eli Lilly (which has made no further submissions since the Court’s judgment in Novartis) have now affirmed, as regards the former issue, that reference may be made in support of product C’s application to product
         B’s data in circumstances where products A and B differ in their pharmaceutical form. 
      
      62.      For several reasons, that conclusion appears to me correct. 
      63.      First, it is not clear whether there is any difference between pharmaceutical form and dosage form, which is specifically
         identified in the Generics judgment as one of the types of variation which is insufficient to merit an additional period of data exclusivity. (27)  Eli Lilly and the Commission both suggest that dosage form is the arcane terminology for pharmaceutical form.  The Notice
         to Applicants makes the same claim. (28)  It is therefore arguable that the question at issue has already been settled by the Court in Generics.  The Court’s reference in that case to the need for essential similarity to be shown must be read, in the light of Novartis, as requiring only essential similarity as between products B and C rather than products A and B. 
      
      64.      Secondly, and in any event, following Novartis, (29) it is clear that the categories of difference expressly identified in the proviso are not the only ones which may separate
         products A and B without excluding the possibility of an applicant in respect of product C relying upon product B’s data.
         
      
      65.      The Court in Novartis specifically confirmed that reference to product B’s data is permissible when products A and B are not bioequivalent, even
         if the difference in bioavailability is not as a consequence of one of the changes identified in the proviso. (30)
      
      66.      The Court reasoned that if an applicant is entitled to refer to data in respect of a variant product which differs from the
         original or reference product in its route of administration or dose, since the differences in those factors generally imply
         that products A and B are not bioequivalent, it must, a fortiori, be able to do so where the original and the variant product are distinguishable only by their different bioavailability,
         even though the route of administration remains the same. (31)
      
      67.      It seems to me that, as APS submitted at the hearing, the same argument can be applied by analogy to a change in pharmaceutical
         form.  A change in the route of administration amounts to a development of the original or reference product so that the data
         submitted in respect of such a variation may be relied upon by a new applicant referencing the original product.  Such a change
         will normally also entail a change of pharmaceutical form.  Thus, in accordance with the Court’s reasoning in Novartis, an applicant must, a fortiori, be able to refer to data in respect of product B where products A and B are distinguishable only by their different pharmaceutical
         forms, even though the route of administration remains the same. 
      
      68.      Thirdly, several of the parties submit that whether a product resulting from the development of the reference medicinal product
         differs in terms of pharmaceutical form does not necessarily bear any relationship to the cost or difficulty involved in that
         development.  The Court in Novartis  found that factor to be relevant when concluding that essential similarity was not always necessary between products A and
         B in order for reliance to be placed on product B’s data. (32)
      
      69.      Finally, the Notice to Applicants identifies pharmaceutical form as one of the types of variation which may exist between
         an original product and what it terms a ‘reference product’ or ‘line extension’ of the original product.  It states that such
         a product may be used by an applicant to claim essential similarity even though it has been authorised for less than 6 or
         10 years, provided that the original product has been authorised for at least that period. 
      
      70.      It is undoubtedly the case that the Notice to Applicants lacks legal force in the sense that it is not in itself legally binding. 
         Nor could it be used to support a position which was clearly at odds with the Directive.  In my view, however, it must be
         accorded some weight when interpreting the Directive.  
      
      71.      In a technically complex field, it seems reasonable to give careful consideration to a document which represents the harmonised
         views of the Commission and the competent authorities of the Member States as to how the Community legislation might workably
         be put into effect.  The Directive itself requires that applications be presented in a way which takes account of the Notice. (33)
      
      72.      Moreover, the Court has emphasised the importance of ensuring a uniform administration of the marketing authorisation regime
         across the Member States. (34)  The Notice to Applicants has an obvious and important role to play in that regard. 
      
      73.      It is therefore unsurprising that the Court has on several occasions in the past had regard to the Notice to Applicants when
         interpreting the Directive. (35)
      
      74.      The only remaining issue to be addressed is whether it is necessary (as the United Kingdom considers) for an applicant wishing
         to refer to product B’s data to proceed under the proviso or whether (as APS, the Commission, Denmark, France and the Netherlands
         contend) the application may be made under the abridged procedure specified in Article 10(1)(a)(iii). 
      
      75.      It would appear that the issue is purely procedural in nature.  I do not take the United Kingdom Government to be suggesting
         that any more data would be required of applicants seeking to rely upon the essential similarity of their product to product
         B if they were made to proceed under the proviso.  The issue is rather one of form. 
      
      76.      The United Kingdom bases its assertion that the proviso is the appropriate procedure upon its reading of the Court’s judgment
         in Novartis. 
      
      77.      It is true that in Novartis, the application to which the main proceedings related had been made under the hybrid abridged procedure. (36)  It is also true that in the relevant passages of the judgment, the Court does incorporate the proviso in its reasoning. (37)
      
      78.      However, the Court’s reasoning in Novartis in relation to the first two questions cannot in my view be read as confined to the proviso. 
      
      79.      It is to be noted that the first two questions referred to the Court in Novartis did not mention the proviso, but were framed instead in terms of the provision which later became Article 10(1)(a)(iii).
         
      
      80.      Moreover, in its discussion of those questions, the Court referred to the proviso only as a basis for identifying categories
         of difference between products A and B which would allow product B legitimately to be considered as a development of product
         A. 
      
      81.      Its analysis involved instead an interpretation of the meaning of medicinal product, as that term appeared in Article 10(1)(a)(iii). 
         The Court concluded that variants of a medicinal product differing in the various respects identified are not sufficiently
         distinct from that product for them to be considered as entirely new products, so as to qualify for their own additional period
         of data exclusivity. (38)
      
      82.      There is thus nothing in the Court’s analysis in Novartis which suggests that it applies only to applications made pursuant to the proviso. 
      
      83.      Indeed, there are good reasons against requiring an application in respect of product C to proceed under the proviso.  The
         proviso operates in circumstances where bridging data are required because of a difference between the new product and the
         earlier product or products to whose data reference is made.  Where product C claims essential similarity to product B which
         is a variant of product A, no additional data are required.  There is therefore no need to proceed under the proviso. 
      
      84.      The Court’s interpretation of Article 10(1)(a)(iii) is to my mind entirely in accordance with the text of that provision. 
         An applicant is still required to show both essential similarity to one or another form of the reference product and that
         the product in question has been authorised within the Community for not less than 6 or 10 years. 
      
      85.      Article 10(1)(a)(iii) nowhere states that the data to which reference is made in support of an application must have been
         submitted to an authority at least 6 or 10 years previously.  Rather, it is the product which must have been authorised for at least that period. 
      
      86.      I note that the approach which I have adopted here arrives at a result which is now explicitly required under the Directive
         as recently amended. (39)  Clearly, earlier versions of the Directive fall to be interpreted independently of such subsequent developments.  None the
         less, I am reassured by the fact that the interpretation of the previously operative provisions which I have proposed has
         recently been explicitly revalidated by the Community legislature. 
      
      87.      For all of the reasons set out above, I am therefore of the view that an applicant seeking the authorisation of product C
         should be permitted to make reference under Article 10(1)(a)(iii) to data submitted in support of an essentially similar product
         B which is a development of another product A, which has been licensed for the requisite period but which differs from product
         A in its pharmaceutical form. 
      
        
       Conclusion 
      88.      It is therefore my opinion that the question referred for a preliminary ruling by the High Court of England and Wales (Queen’s
         Bench Division) should be answered as follows: 
      
      An application for the marketing authorisation for a medicinal product C may be made under Article 10(1)(a)(iii) of Directive
         2001/83/EC, without the need to submit any additional data under the final paragraph of Article 10(1)(a), where the application
         seeks to demonstrate that its new product (product C) is essentially similar to another product (product B) in circumstances
         where: 
      
      –        product B is a new pharmaceutical form of another product (product A) although not essentially similar to product A within
         the meaning of Article 10(1)(a)(iii);  and 
      
      –        product A, but not product B, has been authorised for marketing in the Community for at least the 6 or 10 year period stipulated
         in Article 10(1)(a)(iii). 
      
      1 –	 Original language: English.
      
      2  –	OJ 2001 L 311, p. 67.
      
      3  –	Directive 2004/27/EC of 31 March 2004, OJ 2004 L 136, p. 34.
      
      4  –	Case C-368/96 Generics (UK) and Others [1998] ECR I-7967
      
      5  –	Case C-106/01 Novartis, judgment of 29 April 2004, not yet reported.
      
      6  –	That chapter thereby replaces Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down
         by law, regulation or administrative action relating to proprietary medicinal products, OJ, English Special Edition 1965-1966,
         p. 24, and the amendments thereto.  The provisions of the Directive which are relevant to the present proceedings are in substance
         identical to those previously contained in Directive 65/65/EEC as amended.  
      
      7  –	In paragraphs 38 to 42.
      
      8  –	Previously Article 4(8) of Directive 65/65/EEC.
      
      9  –	That title has been slightly revised as a consequence of the modifications to Annex I of the Directive effected by Commission
         Directive 2003/63/EC of 25 June 2003, OJ 2003 L 159, p 46.
      
      10  –	The Notice to Applicants is regularly updated.  The order for reference cites the May 2001 version.  The most recent version
         dates from February 2004, but does not modify any of the passages relevant to the present proceedings.
      
      11  –	Cited in notes 4 and 5. 
      
      12  –	At paragraphs 31 to 37 and in the operative part of the judgment.
      
      13  –	At paragraphs 28 and 33 of the judgment.
      
      14  –	At paragraph 42 and in the operative part of the judgment.
      
      15  –	At paragraph 47 and in the operative part of the judgment.
      
      16  –	At paragraphs 51 and 52 of the judgment.  Two products are bioequivalent to one another when they have the same bioavailability,
         that is, they are absorbed into the body and transferred to the site of action at the same rate and to the same extent.
      
      17  –	At paragraph 55 and in the operative part of the judgment.
      
      18  –	At paragraphs 53 and 56 and in the operative part of the judgment.
      
      19  –	Paragraphs 61 to 64 of the judgment.
      
      20  –	Paragraphs 57 to 59 of the judgment.
      
      21  –      Paragraph 60 of the judgment.
      
      22  –	Paragraph 67 and the operative part of the judgment.
      
      23  –      Paragraph 66 of the judgment.
      
      24  –	Cited in note 3.
      
      25  –	Cited in note 5.
      
      26  –	Cited in note 5, at paragraphs 61 and 62 of the judgment.
      
      27  –	Cited in note 4, at paragraph 56 of the judgment.
      
      28  –	At section 4.2.2 in Chapter 1 of Volume 2A.
      
      29  –	At paragraphs 65 and 66 of the judgment.
      
      30  –	At paragraph 67 of the judgment.
      
      31  –	At paragraph 66 of the judgment.
      
      32  –	At paragraph 62 of the judgment.
      
      33  –	See paragraphs 14 and 15 above.
      
      34  –	See, for example, Generics, cited in note 4, at paragraphs 48 and 50 of the judgment.
      
      35  –	See, for example, Generics, at paragraph 31 of the judgment, and Novartis, cited in note 5, at paragraph 53.
      
      36  –	Paragraph 16 of the judgment.
      
      37  –	Paragraph 60 of the judgment.
      
      38  –	At paragraph 60 of the judgment.
      
      39  –	See paragraphs 38 to 42 above.