C-106/01

NOVARTIS PHARMACEUTICALS

OPINION OF ADVOCATE GENERAL JACOBS delivered on 23 January 2003 1

1. In the present case the Court of Appeal national licensing authority, processing an of England and Wales (Civil Division) asks application for the marketing authorisation the Court six questions concerning the of a medicinal product pursuant to point 8 conditions which must be met under Com- (a)(iii) of the third paragraph 5of Article 4 munity law before the competent authority of the Directive ('point 8(a)(iii)'), may make in a Member State may authorise the use of data submitted to it by a different marketing of a medicinal product in that applicant in respect of another product Member State. authorised within the six or ten year period specified in that provision. The second issue is whether, in order to obtain authorisation of a new product in reliance on the proviso contained in the final subparagraph of point 8(a) ('the proviso') in conjunction with point 8(a)(i) of the third paragraph of Article 4 ('point 8(a)(1)') or point 8(a)(iii), it is necessary to demonstrate the essential similarity of the new product to the reference product specified pursuant to those latter provisions. The third issue relates to the circumstances in which one 2. In particular, the proceedings raise three product can be said to be 'essentially issues relating to Article 4 of Council similar' to another for the purposes of Directive 65/65/EEC of 26 January 1965 points 8(a)(1) and (iii). on the approximation of provisions laid down by law, regulation and administrative action relating to medicinal products ('the Directive'), 2 as amended by Council Direc- tive 87/21/EEC of 22 December 1986. 3 They allow the Court to consider further the interpretation of that Article which it developed in the Generics case. 4The first issue concerns the circumstances in which a

5. The present proceedings are concerned exclusively with the Community rules — pharmacological and toxicological relating to national authorisations, which tests; at the material time 7were primarily con- tained in Chapter II of the Directive as amended, in particular, by Directive 87/21.

— clinical trials.' 6 — Community-wide authorisations are governed by Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorisation and super- vision of medical products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products, OJ 1993 L 214, p. 1. 7 — The Community legislative framework for medicinal pro- ducts has with effect from 18 December 2001 been codified and consolidated in Directive 2001/83/EC of the European 7. Point 8(a) of the third paragraph of Parliament and of the Council of 6 November 2001 on the Article 4 ('point 8(a)') provides for an Community code relating to medicinal products for human use, OJ 2001 L 311, p. 67. alternative, abridged procedure, whereby, I - 4408

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in certain specified circumstances, an appli- made; ... a Member State may... cant for a marketing authorisation may be extend this period to 10 years by a relieved of the obligation to provide the single Decision covering all the pro- results of pharmacological and toxicologi- ducts marketed on its territory where it cal tests and of clinical trials ordinarily considers this necessary in the interests required by point 8, and may rely instead of public health ...' 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. In order to avail itself of the 'abridged procedure' an 8. The final subparagraph of point 8(a) applicant must demonstrate: contains the following proviso to the abridged procedure established by that provision:

11. The hybrid abridged procedure is therefore intermediate between the abridged and the normal procedure as regards the evidential burden which it imposes on the applicant. The fresh data which an applicant is required to submit 13. The 1993 version of the Notice to pursuant to the hybrid abridged procedure Applicants (volume 2A at paragraph 3.3) are referred to as bridging data. explained the hybrid abridged procedure in the following terms:

That passage has, however, been omitted 16. Annex II to Commission Regulation from subsequent editions of the Notice to (EC) No 541/95 of 10 March 1995 Applicants. concerning the examination of variations to the terms of a marketing authorisation granted by a competent authority of a Member State 10 provides that certain changes to a marketing authorisation, a list of which is set out in that Annex, are to be considered fundamentally to alter the terms of that authorisation and therefore to require an application to vary the terms of 14. The purposes underlying Article 4 are the marketing authorisation. The types of apparent from the preambles to the Direc- change identified in the Annex in respect of tive and to Directive 87/21, which intro- medicinal products for human use are duced the abridged procedures in their changes to the active substance(s) of a current form. The first recital of the product, changes to the therapeutic indica- preamble to the Directive makes clear that tions, and changes to dose, pharmaceutical the primary purpose underlying all the rules form and route of administration. governing the marketing authorisation of medicinal products is the protection of public health. As appears from the second and fourth recitals of the preamble to Directive 87/21, point 8(a)(iii) is also aimed at ensuring that innovative firms are not placed at a disadvantage and at avoiding unnecessary medical testing on humans and animals.

option, pursuant to point 8(a)(iii), to extend 20. As regards the meaning of essential the period specified in that provision from 6 similarity, the Court of Justice held that one to 10 years. medicinal product is essentially similar to another 'where it satisfies the criteria of having the same qualitative and quantita- tive composition in terms of active princi- ples, 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 18. The Court of Justice was called upon to product as regards safety or efficacy'. consider the interpretation of point 8(a)(iii) in the Generics case, 11 which arose out of a challenge brought by several pharmaceuti- cal companies against the decisional prac- tice of the MCA when considering applica- tions for authorisation to market generic copies of existing medicinal products pur- suant to that provision. The MCA had been granting authorisations not only for such 21. As the Court explained, two products indications, dosage schedules, doses or are regarded as being bioequivalent if they dosage forms as had been authorised in are pharmaceutical equivalents or alterna- respect of the reference product for at least tives and if their bioavailabilities (i.e. the 10 years, but also for additions or changes rate and extent of their absorption into the authorised more recently. The MCA would body and transfer to the site of action) after only decline to authorise a generic product administration in the same molar dose are for such additions or changes if they were similar to such a degree that their effects, deemed to constitute major therapeutic with respect to both efficacy and safety, will innovations, such as would necessitate a be essentially the same. new application for marketing authorisa- tion under Annex II to Regulation No 541/95.

provision for all therapeutic indications, are, however, differences between Novartis' dosage forms, doses and dosage schedules first product, Sandimmun, its second pro- already authorised for the reference pro- duct, Neoral, and SangStat's products, duct, including those authorised for less SangCya. When diluted for administration than 6 or 10 years. to the patient, they react differently. Whereas Sandimmun forms a macro-emul- sion in an aqueous environment, Neoral forms a micro-emulsion, and SangCya undergoes a nano-dispersion process. As a consequence, the three products are not bioequivalent: they vary in their bioavail- ability, that is, the rate and extent of their Facts absorption into the body and transfer to the site of action. This is significant because cyclosporin has a narrow therapeutic index if the patient receives too much or too little 23. In the present case, Novartis Pharma- of it, it will not be effective, and may be ceuticals Ltd ('Novartis') challenges the detrimental to health. As a consequence, the validity of marketing authorisations actual level of cyclosporin in the blood of a granted by the MCA to SangStat UK Ltd, patient has to be monitored and the dosage another pharmaceuticals company, and adjusted as necessary. Imtix-SangStat UK Ltd, its distributor in the United Kingdom, in respect of two medicinal products, SangCya Oral Solution and Acceptine Oral Solution (for present purposes identical, and henceforward referred to collectively as SangCya). 26. Sandimmun was the first cyclosporin product to be authorised within the Eur- opean Union. It was authorised in the United Kingdom in 1983 following submis- sion by Sandoz Pharmaceuticals (UK) Ltd, now Novartis, of the complete dossier of 24. SangCya competes on the market with information required under the full proce- two of Novartis' products, Sandimmun and dure. Neoral. All three products are immuno- suppressants, and contain the same active ingredient, cyclosporin, used to prevent rejection of organs or tissue in patients who have undergone transplant surgery, and in the treatment of various auto- 27. Neoral was first authorised for market- immune diseases. ing within the European Union in Germany in 1994. A United Kingdom marketing authorisation was granted in 1995, follow- ing what was apparently a hybrid abridged procedure, made pursuant to point 8(a)(i) in conjunction with the proviso, using 25. Each of the three products is adminis- Sandimmun as the reference product. The tered orally, in the form of a solution. There application therefore partly rested upon

30. Novartis has brought proceedings for judicial review in the United Kingdom courts, seeking an annulment of the MCA's decisions to authorise SangCya on the basis that they are in breach of Community law on one or more of the following three grounds. First, it argues that the MCA was not entitled under point 8(a)(iii) to have regard to data submitted in respect of Neoral prior to the 10th anniversary of 28. The authorisations in respect of Sang- Neoral's first authorisation within the EU Cya, which are at issue in the present (the cross-reference issue). Secondly, it proceedings, were also granted under the argues that the MCA was precluded, as a hybrid abridged procedure, pursuant to matter of law, from finding that SangCya point 8(a)(iii) in conjunction with the was essentially similar to Sandimmun, proviso. The reference product identified thereby excusing SangStat from the require- by SangStat in its application was Sandim- ment to demonstrate that its product was mun, which had been authorised more than safe notwithstanding its lack of bioequiva- 10 years previously. lence with Sandimmun (the essential simi-

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larity issue). Thirdly, it argues that, even if (a) product B was authorised under otherwise lawful, the contested decisions the [point 8(a)] hybrid abridged should be annulled because they infringe procedure, referencing product A; the general principle of non-discrimination, and that similar situations (in this case, the assessment of Neoral and SangCya) should not be treated differently in terms of the data required for authorisation unless such differentiation is objectively justified (the non-discrimination issue).

32. As regards the first of those two questions, the Court of Appeal notes in '1. In considering a marketing authorisa- the order for reference that under Article 5 tion for a new product (C) under of the Directive, a competent authority, [point 8(a)(iii)], referencing a product when deciding upon an application, must (A) authorised more than 6/10 years consider both whether the medicinal pro- ago, is a national competent authority duct is safe and efficacious, and whether the ever entitled to cross-refer, without applicant has submitted all the particulars consent, to data submitted in support and documents required by Article 4 of the of a product (B) which was authorised Directive. In the Court of Appeal's view, within the last 6/10 years? when considering the former issue, it should be open to the competent authority to consider all the data in its possession, regardless of their source. The Court of Appeal therefore requests that, if the Court of Justice concurs, the answer to the first question referred should indicate that any restriction on the data to which the 2. If so, may such cross reference be made authority may make reference relates only in circumstances where: to the latter part of Article 5.

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33. The third question relates to the proper tered to the patient in the form of a interpretation of the proviso, and is as solution diluted to a macro-emulsion, follows: micro-emulsion and nano-dispersion respectively?'

'3. (a) Does the final subparagraph of [point 8(a)] ("the proviso") apply only to applications made under [point 8(a)(iii)] or to applications 35. The sixth and final question relates to made under point [8(a)(1)] also? the non-discrimination issue, and asks whether it is consistent with the general principle of non-discrimination for a national competent authority, faced with hybrid applications for marketing author- isations under point 8(a) referencing pro- (b) Is essential similarity a prerequisite duct A for two other products, neither of for the use of the proviso?' which is bioequivalent to product A:

39. Where the parties differ is as to whether, as the Court of Appeal suggests in the order for reference, a competent authority must also assess whether the Assessment applicant has submitted sufficient evidence to demonstrate that the product is safe and efficacious having regard to the require- ments of Article 4, and, if so, whether the competent authority may at that stage take account of data provided in respect of product B. Three approaches can be dis- tinguished.

Questions 1 and 2 — the cross-reference issue

41. In the United Kingdom's view, a 44. As an alternative submission, Novartis competent authority may therefore rely on suggests that cross-reference is permitted data submitted in respect of product B in only where products A and B meet in full order to authorise product C, a conclusion the requirements of essential similarity to which accords with the Directive's primary one another. Novartis derives support for objective of safeguarding public health, as its alternative submission from paragraph well as with the objective of minimising 55 of the Court's judgment in Generics, in unnecessary testing on humans and ani- which the Court held that the authorisation mals. It thus proposes that the first and of a generic product could extend to second questions should both receive affir- additions or changes to the authorisation mative answers. of its reference product as regards dosage form, dose and dosage schedule granted within the 6 or 10 year period 'assuming that the terms dosage form, dose and dosage schedule as used by the national court do not preclude essential similarity between the medicinal products'.

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product does not meet in full the require- 49. The French Government, SangStat and ments of essential similarity in relation to the Commission prefer instead a formula- product A, provided that any lack of tion whereby cross-reference is permitted if similarity relates to pharmaceutical form, product B constitutes a 'line extension' of therapeutic indication or dose, in other product A. They draw in that regard on the words the types of difference permitted most recent version of the Notice to under the proviso where appropriate bridg- Applicants 13 (in Volume 2A, chapter 1, at ing data have been supplied. In such paragraph 4.2.2), which states that 'the circumstances, it is argued, products A requirement for authorisation for at least and B should still be regarded as essentially 6/10 years in the Community does not the same reference product for the purposes apply to line extensions used as reference of an application under the abridged products beyond the 6/10 years data procedures. exclusivity period of the original medicinal product'.

47. The third approach is favoured by SangStat, the Danish, French, and Nether- lands Governments and the Commission. However, those parties differ somewhat in how they formulate the approach.

51. The difference between the two for- 53. It appears to me that the third mulations of the third approach is more approach is the correct one. apparent than real. The types of variation which are listed in Annex II to Regulations 541/95 and 542/95, and which would not involve the insertion of a new active substance, are changes to the therapeutic indication, changes to dose, pharmaceutical form and route of administration. The 'line 54. In my view, the Court of Appeal and extension' formulation would therefore the parties to the present case are right to permit cross-reference in the same circum- assert that a competent authority may have stances as those specified by the Danish regard to all available data, irrespective of Government. their source, when verifying that a product is safe and efficacious. A competent author- ity must clearly be permitted to decline an application on the strength of data showing a product to be unsafe or lacking in efficacy even if those data were submitted in respect of another product and continue to enjoy protection pursuant to point 8(a)(iii).

59. First, whether a modification of a reference product resulted in a new variant which remained within the bounds of essential similarity would not appear to correlate with the cost or difficulty involved in developing the modification and testing the variant. To accord access to data only 57. I find the second approach equally where the limits of essential similarity had unconvincing. On its primary submission, not been surpassed would therefore intro- Novartis would deny the possibility of duce an arbitrary distinction into the cross-referring to data submitted in respect marketing authorisation regime. of product B even when products A and B are essentially similar to one another. That submission appears to me flatly inconsistent with the Court's conclusions in Generics, which were based on the notion that the essential similarity of the original reference product and its subsequent variants ren- dered them the same product for the purposes of point 8(a)(iii). Following Gen- erics, therefore, cross-reference to product B's data would undoubtedly be possible where product B was essentially similar to 60. Moreover, to limit the application of product A. To exclude the application of the Generics decision to cases where essen- the Generics decision whenever a subse- tial similarity could be shown between the quently authorised variant of a reference original and the variant product would in product had been given a new designation practice largely confine it to new therapeu- would elevate form over substance, and tic indications, given the impact of dosage would create an easy route for applicants to change on quantitative composition, dosage gain additional data protection in circum- form on pharmaceutical form, and both vention of Generics. such changes on bioequivalence.

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66. In my view, essential similarity in all categories of difference which it identifies respects is not required in order for an given the definition of essential similarity application to proceed under the proviso. laid down by the Court in the Generics judgment. A change to the dose of a medicinal product will preclude essential similarity, given that it will constitute a change to the quantitative composition of the product. Similarly, an alteration to the route of administration will in many 67. The purpose of the proviso is to allow instances amount to a modification of an applicant whose product is essentially pharmaceutical form. similar to an existing product except insofar as it differs in one or more of the respects stipulated by the proviso to submit addi- tional or bridging data only with regard to that difference. The relaxation of the criterion of essential similarity in respect of the differences specified in the proviso is possible precisely because the proviso then requires additional bridging data to be Questions 4 and 5 — the essential similarity submitted, thereby assuring that the safety issue and efficacy of the new product can none the less be assessed.

70. The fourth and fifth questions concern the meaning of essential similarity in point 8. Question 4 asks whether bioequivalence 68. The interpretation of the proviso which is always required for a finding that two I propose here accords with that adopted by products are essentially similar. Question 5 the 1993 version of the Notice to Appli- asks what is meant by pharmaceutical form, cants. 17 Whilst subsequent versions of the and more particularly whether products Notice to Applicants have not explicitly have the same pharmaceutical form where endorsed such an interpretation, nor would they are administered to the patient in the they appear to have said anything to form of a solution diluted to a macro- contradict it. emulsion, micro-emulsion and nano-disper- sion respectively.

72. As is clear from the Court's previous case-law, the starting point when interpret- ing the meaning of essential similarity, as with the other requirements laid down by point 8(a), must be to ensure that the requirements of safety and efficacy are at all times maintained in respect of applica- tions pursuant to point 8(a)(i) and (iii) 18 74. It is true, as the United Kingdom and through the specification of standards SangStat point out, that the formulation which are sufficiently precise and detailed contained in the Council's minutes and to ensure a harmonised level of protection. reproduced at paragraph 25 of the Generics judgment states that 'the criteria determin- ing the concept of essential similarity between medicinal products are that they have the same qualitative and quantitative composition in terms of active principles and the same pharmaceutical form, and, where necessary, bioequivalence of the two 73. To that end, the Court in Generics products has been established by appro- adopted a definition of essential similarity priate bioavailability studies'.19In reliance drawn from the minutes of the meeting of on the italicised passage, the United King- the Council in December 1986 at which dom and SangStat assert that bioequiva- Directive 87/21 was adopted. As set out in lence is not an invariable requirement for a the operative part of the judgment, its finding of essential similarity. I do not definition specifies bioequivalence together accept their interpretation of that passage. with pharmaceutical form and qualitative In my view, it is intended only to indicate and quantitative composition as criteria that bioavailability studies will not always which the competent authority of a Mem- be required in order to demonstrate bioe- ber State may not disregard when determin- quivalence in cases where bioequivalence is in any event clear.

75. The United Kingdom Government and 77. It is therefore my opinion that bioequi- SangStat submit also that bioequivalence valence is a necessary requirement of will not always be a relevant criterion in essential similarity. order to determine whether two products are equally safe and efficacious, and that therefore it should not constitute an inflex- ible requirement of essential similarity. Such is the case, they suggest, with cyclosporin products, given that doctors must regularly 78. As regards the proper meaning of measure the levels of cyclosporin in a pharmaceutical form, Advocate General patient's blood and adjust doses accord- Ruiz-Jarabo Colomer in the Generics case ingly. I am unconvinced, however, that it defined it, in my view correctly, as the would not be necessary, at least when fixing combination of the form in which a for a patient the initial dosage of a new pharmaceutical product is presented by a product claiming essential similarity to an manufacturer (the form of presentation) existing product, to be confident of the two and the form in which it is administered products' bioequivalence. (the form of administration).21'He drew the definition from the European Pharmaco- poeia, inaugurated by the Council of Europe in 1964 for the purposes of laying down common standards for the composi- tion and preparation of substances used in the manufacture of medicines. Applicants are required in a number of respects by the 76. The United Kingdom further submits Annex to Directive 75/318/EEC to prepare that in respect of certain types of product, the particulars and documents for submis- the criterion of bioequivalence is inapplic- sion pursuant to Article 4 of the Directive in able because they owe their therapeutic accordance with the standards laid down effect to topical application rather than by the European Pharmacopoeia. transmission via systemic circulation. I find that submission equally unconvincing. It appears from the Community Guidelines relating to the investigation of bioavailabil- ity and bioequivalence that whilst the approach commonly used to determine 79. The definition supplied by the Eur- systemic bioavailability cannot be opean Pharmacopoeia does not, however, employed in such cases, local availability indicate with what degree of specificity the may still be assessed using measurements form of presentation and the form of quantitatively reflecting the presence of the administration must be described. It there- active substance at the site of action, arrived fore does not in itself resolve the disagree- at by methods specially chosen for the ment between the parties to the present particular combination of active substance proceedings as to whether the products in and localisation in question. 20 question may all be given the label of oral solution or whether it is instead necessary

84. By its sixth question, the Court of Appeal seeks to ascertain whether there is any breach of the general principle of non- 82. Novartis disagrees with the Commis- discrimination for a competent authority, sion, pointing out that differences between considering two hybrid applications refer- encing product A for two products, B and C, neither of which is bioequivalent to 22 — In volume 2A, chapter 1, paragraph 4.2. product A, to require full clinical data

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competent authority may refer to all available data when assessing the safety and efficacy of that product.

If the application pertains to a new product C and is made under point 8(a) (iii) of the third paragraph of Article 4, making reference to a product A which was authorised more than 6/10 years previously, a competent authority is entitled, when verifying that the documents and particulars submitted in support of the application comply with Article 4, to cross-refer to data submitted in support of product B which was authorised within the previous 6/10 years, without consent of the person responsible for the marketing of product B, provided that products A and B are essentially similar or differ only in respect of their pharmaceutical form, dose, or therapeutic use.

(2) The proviso in the final subparagraph of point 8(a) of the third paragraph of Article 4 of Directive 65/65 applies to applications made under point 8(a)(i) and (iii) of that paragraph. In order for an application to be made under the proviso in respect of a new product C making reference to a product A, product C must be essentially similar to product A except insofar as it differs in one or more of the respects specified by the proviso.

(3) For two products to be essentially similar within the meaning of point 8(a) of the third paragraph of Article 4 of Directive 65/65, they must be bioequivalent.