62001CC0223_EN
Opinion of the Advocate-General
Opinion of the Advocate-General
1.
In this case the Østre Landret (Eastern Regional Court), Denmark, has referred two questions on the interpretation 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.
(2)
2.
The questions concern in particular the so-called ‘abridged procedure’ provided under point 8(a)(iii) of the third paragraph
(3) of Article 4 of Directive 65/65 (‘point 8(a)(iii)’), which envisages that, where a marketing authorisation has been issued for a given medicinal product, an application for a marketing authorisation for a generic version of that product may in certain circumstances be made on the basis of a procedure which is simpler than the procedure for obtaining the initial marketing authorisation.
3.
In order for the abridged procedure provided by point 8(a)(iii) to be available, the product for which authorisation is sought must be shown to be essentially similar to another product (‘the reference product’) which has been authorised in the Community for a period of either 6 or 10 years.
It is a further condition for the use of that procedure that the reference product be marketed in the Member State for which the application is made.
The referring court considers that it is unclear when that marketing condition must be satisfied:
must the reference product be marketed when the application for the generic authorisation is made and/or when the generic authorisation is granted or is it sufficient that it has been marketed at some point before the application is made?
The referring court also asks for guidance on the meaning of ‘marketed’.
The relevant EC legislation
4.
The preamble to Directive 65/65 states:
‘… the primary purpose of any rules concerning the production and distribution of medicinal products must be to safeguard public health;
… however, this objective must be attained by means which will not hinder the development of the pharmaceutical industry or trade in medicinal products within the Community …’.
(4)
5.
Under Article 3 of Directive 65/65, no medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued by the competent authorities of that Member State or an authorisation has been granted in accordance with Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products.
(5)
6.
Under Article 4 of Directive 65/65, the person responsible for placing a medicinal product on the market is to make application to the competent authority of the Member State concerned. The application is to be accompanied by a number of prescribed particulars and documents, including, under point 8 of the third paragraph of Article 4, results of physico-chemical, biological or microbiological tests, pharmacological and toxicological tests and clinical trials.
7.
Point 8(a), however, provides for an abridged application or simplified procedure to be available by way of exception in certain circumstances.
In so far as relevant, point 8(a) provides as follows:
‘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:
…
(iii))… that the proprietary 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; ....’.
8.
Point 8(a)(iii) was introduced by Directive 87/21,
(6) the preamble to which states:
‘… experience has shown that it is advisable to stipulate more precisely the cases in which the results of pharmacological and toxicological tests or clinical trials do not have to be provided with a view to obtaining authorisation for a medicinal product which is essentially similar to an authorised product, while ensuring that innovative firms are not placed at a disadvantage;
…
… there are reasons of public policy for not conducting repetitive tests on humans or animals without over-riding cause’.
(7)
9.
Point 11 of the third paragraph of Article 4 of Directive 65/65 includes among the documents to be submitted by an applicant for a marketing authorisation copies of any marketing authorisation obtained in another Member State for the product concerned;
that information is to be updated on a regular basis.
10.
Under Article 5 of Directive 65/65, authorisation is to 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.’
11.
Article 9a of Directive 65/65 provides as follows:
‘After an authorisation has been issued, the person responsible for placing the product on the market must, in respect of the methods of preparation and control provided for in points 4 and 7 of the [third] paragraph of Article 4, take account of technical and scientific progress and introduce any changes that may be required to enable that medicinal product to be manufactured and checked by means of generally accepted scientific methods. …’
(8)
12.
The first paragraph of Article 11 of Directive 65/65 provides:
‘The competent authorities of the Member States shall suspend or revoke an authorisation to place a proprietary medicinal product on the market where that product proves to be harmful in the normal conditions of use, or where its therapeutic efficacy is lacking, or where its qualitative and quantitative composition is not as declared.
…’
13.
Article 21 of Directive 65/65 provides that an authorisation to market a medicinal product is not to be refused, suspended or revoked except on the grounds set out in the Directive.
14.
Article 1 of Directive 75/318
(9) provides:
‘Member States shall take all appropriate measures to ensure that the particulars and documents which must accompany applications for authorisation to place a medicinal product on the market (marketing authorisation), pursuant to point … 8 of Article 4, [third] paragraph, of Directive 65/65/EEC, are submitted by the persons concerned in accordance with the Annex to this Directive.
…’
15.
The introduction to that Annex
(10) includes the following statement:
‘… in order to monitor the benefit/risk assessment after marketing authorisation has been granted, any change to the data in the dossier, any new information not in the original application and all pharmacovigilance reports, shall be submitted to the competent authorities.’
16.
At the relevant time, Council Directive 75/319
(11) provided as follows, in so far as relevant:
‘Article 4
In order to examine the application submitted in accordance with Article 4 of Directive 65/65/EEC, the competent authorities of the Member States:
(a))must verify whether the particulars submitted in support of the application comply with the said Article 4 and examine whether the conditions for issuing an authorisation to place medicinal products on the market (marketing authorisation) are complied with; …
…
Article 29a
In order to ensure the adoption of appropriate regulatory decisions concerning the medicinal products authorised within the Community, having regard to information obtained about adverse reactions to medicinal products under normal conditions of use, the Member States shall establish a pharmacovigilance system. This system shall be used to collect information useful in the surveillance of medicinal products, with particular reference to adverse reactions in human beings, and to evaluate such information scientifically.
Such information shall be collated with data on consumption of medicinal products.
This system shall also collate information on frequently observed misuse and serious abuse of medicinal products.
Article 29b
For the purpose of this Directive, the following definitions shall apply:
–“adverse reaction” means a reaction which is harmful and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or treatment of disease or the modification of physiological function,
–“serious adverse reaction” means an adverse reaction which is fatal, life-threatening, disabling, incapacitating, or which results in or prolongs hospitalisation,
–“unexpected adverse reaction” means an adverse reaction which is not mentioned in the summary of product characteristics,
–“serious unexpected adverse reaction” means an adverse reaction which is both serious and unexpected.
Article 29c
The person responsible for placing the medicinal product on the market shall have permanently and continuously at his disposal an appropriately qualified person responsible for pharmacovigilance.
That qualified person shall be responsible for the following:
(a))the establishment and maintenance of a system which ensures that information about all suspected adverse reactions which are reported to the personnel of the company, and to medical representatives, is collected and collated at a single point within the Community;
(b))the preparation for the competent authorities of the reports referred to in Article 29d, in such form as may be laid down by those authorities, in accordance with the relevant national or Community guidelines;
(c))ensuring that any request from the competent authorities for the provision of additional information necessary for the evaluation of the benefits and risks afforded by a medicinal product is answered fully and promptly, including the provision of information about the volume of sales or prescriptions of the medicinal product concerned.
Article 29d
1..The person responsible for placing the medicinal product on the market shall be required to record and to report all suspected serious adverse reactions which are brought to his attention by a health care professional to the competent authorities immediately, and in any case within 15 days of their receipt at the latest.
22In addition, the person responsible for placing the medicinal product on the market shall be required to maintain detailed records of all other suspected adverse reactions which are reported to him by a health care professional.
Unless other requirements have been laid down as a condition of the granting of authorisation, these records shall be submitted to the competent authorities immediately upon request or at least every six months during the first two years following authorisation, and once a year for the following three years. Thereafter, the records shall be submitted at five-yearly intervals together with the application for renewal of the authorisation, or immediately upon request. These records shall be accompanied by a scientific evaluation.
Article 29e
The Member States shall take all appropriate measures to encourage doctors and other health care professionals to report suspected adverse reactions to the competent authorities.
The Member States may impose specific requirements on medical practitioners, in respect of the reporting of suspected serious or unexpected adverse reactions, in particular where such reporting is a condition of the authorisation.
Article 29f
The Member States shall ensure that reports of suspected serious adverse reactions are immediately brought to the attention of the [European Agency for the Evaluation of Medicinal Products] and the person responsible for placing the medicinal product on the market, and in any case within 15 days of their notification, at the latest.
Article 29g
In order to facilitate the exchange of information about pharmacovigilance within the Community, the Commission, in consultation with the Agency, Member States and interested parties, shall draw up guidance on the collection, verification and presentation of adverse reaction reports.
This guidance shall take account of international harmonisation work carried out with regard to terminology and classification in the field of pharmacovigilance.
Article 29h
Where as a result of the evaluation of adverse reaction reports a Member State considers that a marketing authorisation should be varied, suspended or withdrawn, it shall forthwith inform the Agency and the person responsible for placing the medicinal product on the market.
In case of urgency, the Member State concerned may suspend the marketing of a medicinal product, provided the Agency is informed at the latest on the following working day.
…
Article 33
…
2..The person responsible for the marketing of a medicinal product shall be obliged to notify the Member States concerned forthwith of any action taken by him to suspend the marketing of a product or to withdraw a product from the market, together with the reasons for such action if the latter concerns the efficacy of the medicinal product or the protection of public health. …’
The facts and the questions referred
17.
The present case concerns the medicinal product Losec.
Losec, reportedly the world’s largest-selling pharmaceutical, is used to treat and prevent peptic ulcers and reflux oesophagitis (heartburn).
It contains omeprazole, a substance called a proton-pump inhibitor which works by blocking a particular mechanism in the stomach called the proton pump which controls acid production, thereby reducing the amount of stomach acid produced.
18.
Losec Enterokapsler (Losec entero-capsules;
‘Losec capsules’) were developed by the Astra group and have been approved and marketed in Denmark since 1989.
On 3 February 1997 AstraZeneca A/S, a Danish company in the Astra group, applied to the Lægemiddelstyrelse (the Danish competent authority for the purpose of Directive 65/65) for approval for Losec Enterotabletter (Losec entero-tablets;
‘Losec tablets’).
The Lægemiddelstyrelse issued a marketing authorisation for Losec tablets on 22 September 1997.
19.
By letter of 3 October 1997 AstraZeneca gave notice that it proposed to withdraw Losec capsules from the market in Denmark from 6 April 1998.
The notice concerning withdrawal was repeated on 19 March 1998 and the marketing authorisation was withdrawn on 6 April 1998. Approval of the medicinal product in Denmark thus lapsed in Denmark.
It is common ground that the withdrawal of marketing authorisation for Losec capsules was not based on considerations of public health.
20.
AstraZeneca has explained before the national courts that Losec capsules continue to be approved and marketed in Austria, France, Greece, Ireland, Italy, Luxembourg, Portugal, and the United Kingdom.
In some of those Member States, Losec capsules are marketed alongside Losec tablets.
It appears to be accepted that Losec tablets and Losec capsules are what are known as therapeutic equivalents – that is to say, they contain the same active ingredient (omeprazole) – and are bioequivalent in that that ingredient is absorbed by the body at the same rate and to the same extent when taken orally.
It appears that, in addition to their different presentation, the products differ in the form of the active ingredient (magnesium salt of omeprazole acid as opposed to omeprazole acid).
It should be noted that the question whether Losec capsules are ‘essentially similar’ to Losec tablets within the meaning of point 8(a)(iii) is not at issue in the present case, which concerns solely the interpretation of the marketing condition in that provision.
21.
On 23 February 1998 Generics UK Ltd applied to the Lægemiddelstyrelse for marketing authorisation for Omeprazol Generics Enterokapsler (Entero-capsules).
That product is a generic medicinal product and the application for marketing authorisation was submitted as an abridged application pursuant to point 8(a)(iii).
The reference product for Omeprazol Generics Entero-capsules was Losec capsules.
22.
The Lægemiddelstyrelse approved and issued marketing authorisation for Omeprazol Generics Entero-capsules on 30 November 1998.
23.
AstraZeneca sought judicial review of the Lægemiddelstyrelse's decision of 30 November 1998 before the Østre Landsret, arguing in particular that point 8(a)(iii) requires that there must be a valid marketing authorisation for the reference product both when the application for the authorisation for the generic product is submitted and when the generic authorisation is issued.
24.
The Lægemiddelstyrelse contended in contrast that point 8(a)(iii) should be interpreted as meaning that it is a necessary and sufficient condition that there be a marketing authorisation for the reference product at the time of the application.
25.
Generics UK Ltd intervened in support of the Lægemiddelstyrelse.
26.
The Østre Landsret considers that the Danish version of point 8(a)(iii) is not wholly clear on this point:
there is disagreement as to whether the auxiliary verb ‘har været’ (has been) relates simply to the condition that the reference product has been approved in the Community or relate also to the condition of being marketed in the Member State for which the application is made.
27.
The Østre Landsret adds that there is moreover disagreement between the parties on the interpretation of the term ‘marketed’ in point 8(a)(iii).
28.
The order for reference also describes parallel national proceedings before the Østre Landsert between another generics manufacturer, A/S GEA Farmaceutisk Fabrik, and the Lægemiddelstyrelsen, originally also the subject of the same reference for a preliminary ruling.
That manufacturer however has discontinued its action before the Østre Landsret which has consequently notified the Court that (i) A/S GEA Farmaceutisk Fabrik is no longer to be regarded as a party to the proceedings and (ii) the first part of the first question together with the third question originally referred have been withdrawn since they are not relevant to the proceedings between AstraZeneca and the Lægemiddelstyrelsen.
29.
The Østre Landsret notes in conclusion that although in
Generics (12) the Court of Justice ruled on the substantive conditions in point 8(a)(iii) governing whether a medicinal product ‘is essentially similar to’ the reference product, the Court has not yet ruled on the provision's conditions as to time.
It has accordingly referred the following questions to the Court for a preliminary ruling:
‘1..In a case where an undertaking applies for marketing authorisation on the basis of an abridged application (simplified procedure) under Article 4, third paragraph, point 8(a)(iii) of the first medicinal products directive (Council Directive 65/65/EEC as subsequently amended) and states that the product for which marketing authorisation is sought is essentially similar to a reference product which has been approved in the Community for the necessary period of time pursuant to the directive, is it necessary and sufficient that the reference product:
… (13)
(b))at the time of the application is still being marketed in the Member State for which the application is made, or
(c))is still being marketed at the time of the application and at the time of grant of the marketing authorisation in the Member State for which the application is made?
2..Does the term “marketed” in Article 4, third paragraph, point 8(a)(iii) mean that it is sufficient and necessary that there be approval in the form of marketing authorisation for the reference product in the Member State for which the application is made?’
The first question
30.
By its first question the referring court asks essentially whether on an application for marketing authorisation under point 8(a)(iii) the reference product must be marketed both at the time of the application and at the time of grant of the authorisation or merely at the time of the application.
31.
The first question as originally formulated also provided a third option, asking whether it was sufficient that the reference product had been marketed at some point before the application was made.
That part of the first question was however withdrawn by the national court since it was prompted by the proceedings then pending before it between A/S GEA Farmaceutisk Fabrik and the Lægemiddelstyrelsen which were subsequently discontinued.
None the less the third option set out in the first question as originally formulated represents a possible interpretation of point 8(a)(iii) and is moreover the interpretation advocated by Generics, the Netherlands Government and the EFTA Surveillance Authority.
I will accordingly not rule it out at this stage.
Observations of the parties
32.
Written observations have been submitted by AstraZeneca, Generics (intervener before the national court), the Danish Government both in its capacity as a Member State and on behalf of the Lægemiddelstyrelsen, the Netherlands and Norwegian Governments, the Commission and the EFTA surveillance authority, all of which with the exception of the Netherlands Government were represented at the hearing.
33.
AstraZeneca considers that, in order for a marketing authorisation to be valid in accordance with point 8(a)(iii), the reference product must be marketed both when the application is made and when the authorisation is granted.
34.
Generics, the Netherlands Government and the EFTA Surveillance Authority consider that it is sufficient that the reference product has been marketed at some point in the Member State for which application is made;
it is not necessary for it to be marketed when the application is made or when the authorisation is granted.
35.
The Danish and Norwegian Governments and the Commission consider that the reference product must still be marketed in the Member State for which the application is made at the time of the application.
36.
AstraZeneca supports its view principally by reference to public health concerns.
It notes that once a marketing authorisation has been granted for the generic product, the holder of that authorisation is obliged to monitor use of the product and provide up-to-date information with regard to pharmacovigilance and other data which are important for assessing the safety and efficacy of the product.
Until the authorisation for the generic product is granted, the competent authority in the Member State where the application for that authorisation is made – which is required to assess whether the quality, safety and efficacy criteria are satisfied when the authorisation is granted – will have to rely on the existence of an authorisation for the reference product and the resulting obligations on its holder.
When the authorisation for the reference product is withdrawn, all those pharmacovigilance obligations disappear and the competent authority cannot therefore count on the particulars and documents available to it being complete and up-to-date. Although it may be argued that the competent authority will still have files which it may itself update by obtaining information from other Member States on the basis of the normal cooperation between Member States, AstraZeneca submits that that cooperation assumes that the authorisation is maintained in other Member States, which will not necessarily be the case;
the interpretation of the conditions of application of the abridged procedure cannot depend on the existence of specific facts which may not occur.
37.
Generics, the Netherlands Government and the EFTA Surveillance Authority seek to counter those arguments by reference in particular to the pharmacovigilance requirements imposed by Directive 75/319
(14) which subsist even after withdrawal of the original authorisation.
The Netherlands Government submits that when there is no authorisation for a given medicinal product, that product cannot be sold and there can therefore be no new information on side-effects and adverse reactions.
It notes that in any event it is not only the holder of an authorisation who is bound to report suspected adverse reactions to the competent authorities since Article 29e of Directive 75/319 requires the Member States to take all appropriate measures to encourage doctors and other health care professionals to make such reports.
In addition the Member States are to inform each other pursuant to Article 29f of all adverse reactions.
The competent authorities are therefore in a position to keep the file up-to-date even where there is no national authorisation.
Generics and the EFTA Surveillance Authority also stress that data may be obtained by cooperation with the competent authorities of the Member States where the capsules continue to be marketed.
38.
Those parties submit further that if it were a condition for the grant of a generic authorisation that the reference product be marketed when the application for that authorisation was filed, the manufacturer of the reference product could effectively bar generic manufacturers from using the abridged procedure and thereby render point 8(a)(iii) redundant.
That would run counter to the aims of point 8(a)(iii) as set out in the preamble to Directive 87/21
(15) which include the reduction of animal and human testing (required to support an application under the full procedure).
The Netherlands Government adds that it is also apparent from the preamble to Directive 87/21 that point 8(a)(iii) seeks to stipulate precisely the cases in which the abridged procedure may be used.
Differences in the way in which the abridged procedure is applied in the different Member States must therefore be prevented.
If the provision is interpreted so that a generic product may be marketed in one Member State but not in another for the sole reason that the reference product is no longer marketed in the latter Member State when the application for authorisation is made, the effect would be to fragment the internal market in medicinal products, which cannot have been intended by the legislation.
39.
The Norwegian Government and the Commission also take the view that, where the marketing authorisation for the reference product is withdrawn before the generic authorisation is issued but the reference product is still marketed in other Member States, the competent authority of the Member State where application is made can satisfy its pharmacovigilance duties by virtue of the exchange of information provided for by Directive 75/319;
moreover that authority will still have the file for the original full application. The Danish Government however does not consider it relevant whether the reference product is still marketed in other Member States, noting that Directive 65/65
(16) – in contrast to Regulation No 2309/93
(17) which provides for a central marketing authorisation – set up a system under which the authorities of each Member State issue authorisations for medicinal products marketed in that State.
The Danish Government considers that public health is none the less safeguarded since all the necessary information concerning the reference product is available to the competent authority of the Member State in which application for the generic authorisation is made, that product having been authorised on the basis of a complete application.
The national authorities can thus control what is put on the market and no product can be put on the market unless those authorities have dealt at least once with a complete application procedure.
It is precisely because the authorities have the necessary information that the abridged procedure is applicable.
40.
The Danish Government and the Commission submit that the wording of point 8(a)(iii) in the English, French and German versions is clear.
The Commission adds that Article 4 of Directive 65/65 concerns solely the conditions of applying for a marketing authorisation and accordingly does not concern the issue of that authorisation.
Since the time the application is made is decisive for determining whether the conditions of issue of the authorisation for a generic product are satisfied, the marketing authorisation for the reference product must be in force when that application is made.
The Danish and Norwegian Governments also consider that the interpretation advocated by AstraZeneca would enable the holder of a marketing authorisation to block generic copies by withdrawing that authorisation.
Assessment
41.
The text of the relevant phrase in point 8(a)(iii) reads as follows:
‘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 … that the medicinal product is essentially similar to a product which … is marketed in the Member State for which the application is made’.
Generics, focusing in particular on the English version, describes that wording as ‘at best unclear and at worst ambiguous as to the marketing requirements in the Member State concerned’.
After an exhaustive analysis of the objectives and legislative history of Directive 87/21,
(18) which introduced the provision, Generics concludes that point 8(a)(iii) should be interpreted as requiring that the reference product must have been at least some time previously authorised prior to the filing of the generic application in the Member State concerned.
That view is shared by the Netherlands Government and the EFTA Surveillance Authority.
42.
I disagree.
While it may not be clear from the wording of point 8(a)(iii) whether it speaks from the time the application for the generic authorisation is lodged or the time the generic authorisation is granted, the provision cannot to my mind bear the meaning ascribed to it by Generics.
If the applicant has to demonstrate that the reference product ‘is marketed’, he cannot do so by demonstrating that it ‘has been marketed’ at some time but no longer is marketed:
the two are not synonymous.
43.
That interpretation follows unequivocally from the English version.
It is also supported, as the Danish Government and the Commission submit, by the French and German versions:
on a natural reading the temporal condition there spelt out
(19) could not be satisfied by showing that the reference product had been marketed at some time before the application for the generic authorisation was made but was no longer marketed when that application was made.
It may be noted that the EFTA Surveillance Authority concedes that a literal interpretation of point 8(a)(iii) entails that conclusion.
44.
Accordingly I reject the solution proposed by Generics, the Netherlands Government and the EFTA Surveillance Authority and envisaged by the referring court in its withdrawn question 1(a).
45.
Nor do I accept the interpretation advocated by AstraZeneca, namely that, in order for a marketing authorisation to be valid in accordance with point 8(a)(iii), the reference product must be covered by a marketing authorisation both when the application is made and when the authorisation is granted.
To my mind the scheme of the provision precludes such an interpretation.
As the Commission points out, Article 4 of Directive 65/65 is concerned with the procedure for applications for abridged authorisations.
The first paragraph provides that, in order to obtain an authorisation to place a medicinal product on the market, the person responsible for placing that product on the market is to make application to the competent authority of the Member State concerned.
The third paragraph requires the application to be accompanied by specified particulars and documents.
Those particulars and documents clearly speak from the time the application is made.
They include, under point 8 of the third paragraph of Article 4, results of physico-chemical, biological or microbiological tests, pharmacological and toxicological tests and clinical trials.
Point 8(a)(iii) states that the applicant ‘shall not be required to provide the results of [those tests and trials] if he can demonstrate … that the medicinal product is essentially similar to a product which … is marketed in the Member State for which the application is made’.
I can see nothing in the scheme or wording of the provision to support the view that that requirement to demonstrate that the reference product is marketed continues until the generic authorisation is granted.
46.
AstraZeneca argues with some vigour that if its interpretation is not endorsed by the Court, the competent authority of the Member State for which the application is made will be unable to discharge its duties of pharmacovigilance.
That argument appears to be based in particular on two provisions of the legislation.
Before turning to the substance of AstraZeneca’s concerns, I will look at the text of those provisions.
47.
First, AstraZeneca refers to Article 4(a) of Directive 75/319,
(20) which requires the competent authorities of the Member States to ‘examine whether the conditions for issuing an authorisation to place medicinal products on the market … are complied with’.
AstraZeneca maintains that that provision requires the competent authorities to verify whether the criteria of quality, safety and efficacy are satisfied when the authorisation is issued.
48.
I am not convinced that as a matter of construction Article 4(a) bears that meaning.
The full text is as follows:
‘In order to examine the application submitted in accordance with Article 4 of Directive 65/65/EEC, the competent authorities of the Member States:
(a) must verify whether the particulars submitted in support of the application comply with the said Article 4 and examine whether the conditions for issuing an authorisation to place medicinal products on the market … are complied with’.
A natural reading of the provision suggests to me that it speaks from when the application is made.
49.
Second, AstraZeneca bases its argument on Article 5 of Directive 65/65
(21) which lists the circumstances in which a competent authority is to refuse to issue a marketing authorisation. The first paragraph of that article requires authorisation to 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’.
AstraZeneca submits that the competent authority will be unable to assess whether the quality, safety and efficacy criteria are satisfied when the authorisation is granted unless the reference product continues to be marketed up to that point.
50.
Again I am not convinced that as a matter of construction the first paragraph of Article 5 supports that view:
since the particulars and documents referred to are required to be submitted with the application, the most natural interpretation of the provision is that it speaks as from the moment when the application is made.
Moreover, since an applicant for a generic authorisation is relying on an express exemption from the obligation to provide specified particulars and documents, it seems somewhat circular to invoke Article 5 as a basis for refusing the authorisation on the ground that those same particulars and documents cannot be updated by the applicant after he has lodged his application.
51.
However, it is clear that the primary purpose of the Community legislation on the marketing of medicinal products is to safeguard public health.
(22)
The substance of AstraZeneca’s argument is that its interpretation must prevail if public health is not to be prejudiced, and in particular that, when the authorisation for the reference product is withdrawn, the competent authority is not in a position to ensure that it is in possession of up-to-date information on the quality, safety and efficacy of the reference product when it grants the generic authorisation
52.
I do not accept that argument.
53.
First, the person responsible for placing the product on the market is required by Article 29c of Directive 75/319
(23) to provide for the collection and collation at a single point within the Community of information about all suspected adverse reactions reported to it and to ensure that any request from the competent authorities for the provision of additional information necessary for the evaluation of the benefits and risks of the product is answered fully and promptly.
Thus the competent authority of the Member State where an application under the abridged procedure is made may, if it considers it appropriate, approach the company which holds the marketing authorisation for the reference product in another Member State before issuing an authorisation for the generic product.
54.
Second, Article 29d of Directive 75/319
(24) requires the person responsible for placing the product on the market to record and promptly report to the competent authorities all suspected serious adverse reactions brought to his attention by a health care professional and to maintain detailed records of all other suspected adverse reactions so reported.
Those records are to be submitted to the competent authorities at periodic intervals but at any event ‘immediately on request’.
55.
It may be noted that the Member States are to take all appropriate measures to encourage doctors and other health care professionals to report suspected adverse reactions to the competent authorities
(25) and to ensure that reports of suspected serious adverse reactions are immediately brought to the attention of the Agency and the person responsible for placing the medicinal product on the market.
(26)
56.
AstraZeneca itself stresses the rigour of those requirements in its written observations in support of its argument that up-to-date information will not be available to the competent authority of the Member State where application for a generic authorisation is made once the marketing authorisation for the reference product has been withdrawn.
The abovementioned pharmacovigilance obligations will however continue to apply for so long as the reference products have marketing authorisations in other Member States.
57.
An analogy may be drawn with the situation of a parallel importer where the marketing authorisation for the reference product is withdrawn for reasons unconnected with the safety of the product.
Although it is clear from the case-law of the Court that the parallel import of medicinal products is not governed by Directive 65/65,
(27) the question whether in such circumstances adequate pharmacovigilance may be ensured by the competent authority of the Member State of import in the absence of a marketing authorisation for the reference product has arisen.
The Court stated in
Ferring (28) that, although adequate monitoring of the old version remained necessary in the State of import, pharmacovigilance satisfying Directive 75/319 could ordinarily be guaranteed through cooperation with the national authorities of the other Member States by means of access to the documents and data produced by the manufacturer or other companies in the same group, relating to the old version in the Member States in which that version was still marketed on the basis of a marketing authorisation still in force.
58.
AstraZeneca also makes the point that the competent authority dealing with an application for authorisation will be aware of the existence of marketing authorisations in other Member States since point 11 of the third paragraph of Article 4 of Directive 65/65 requires the applicant to submit copies of any authorisation obtained in another Member State and moreover regularly to update that information.
59.
Admittedly, as AstraZeneca states, the abovementioned pharmacovigilance obligations will subsist only as long as the reference product continues to be marketed in at least one other Member State.
AstraZeneca argues that where that situation does not obtain there will be a lacuna:
the competent authority to which application for a generic authorisation is made cannot satisfy itself that its pharmacovigilance information is up-to-date before issuing the generic authorisation.
60.
However, as the Netherlands and Norwegian Governments submit, it is also true that for as long as neither the reference product nor the generic product is being marketed in the Community there will be no adverse reaction reports to be made.
Since in such circumstances therefore the concept of pharmacovigilance information being up-to-date is meaningless, it is incorrect to conclude that the competent authority of the Member State in which an application for a generic authorisation is made will be unable for that reason to comply with its pharmacovigilance duties if the marketing authorisation for the reference product is withdrawn before the generic authorisation is issued.
61.
Of course if the marketing authorisation for the reference product is withdrawn on grounds of public health, it would clearly be inappropriate for a generic authorisation to be issued after withdrawal of the earlier authorisation.
However, since – as AstraZeneca points out in its written observations – Article 33(2) of Directive 75/319 requires the person responsible for the marketing of a medicinal product immediately to notify the Member States concerned if he withdraws the product from the market, giving reasons if they concern the protection of public health, the competent authority to which the application for a generic authorisation is made will be in a position to make that assessment.
62.
The interpretation of point 8(a)(iii) which I propose reflects to my mind the objectives of that provision as set out in the preamble to Directive 87/21,
(29) which introduced it.
In particular, as the Netherlands Government stresses, it ensures that there is no unnecessary duplication of tests on humans or animals, which would be required if the applicant for a generic authorisation were unable to rely on the abridged procedure where the marketing authorisation for the reference product was withdrawn after his application had been lodged.
The need to ensure that innovative firms are not placed at a disadvantage, also mentioned in the preamble to Directive 87/21, is of course ensured by the requirement in point 8(a)(iii) that the reference product has been authorised in the Community for a period of 6 or 10 years;
moreover patent rights are protected independently of the regulation of medicinal products.
63.
That interpretation is also consistent with the understanding of the provision on which the Commission has based its published guidance in
The Rules governing Medicinal Products in the European Community
, Volume 2,
Notice to applicants for marketing authorisations for medicinal products for human use in the Member States of the European Community
.
That guide reflects the consensus of the Member State representatives on the Committee for Proprietary Medicinal Products and the European Agency for the Evaluation of Medicinal Products established by Regulation No 2309/93.
(30)
Volume 2A of those Rules is entitled Procedures for marketing authorisation, and in its current version
(31) states:
‘Competent authorities must check that a product, to which reference is made, is still authorised
at the time of application
.
If the [reference] authorisation is withdrawn after a generic … application has been lodged but before the authorisation has been granted, competent authorities may nevertheless grant the generic marketing authorisation if there are no public health concerns which lead [sic] to the withdrawal/suspension of the original product.’
(32)
64.
It is also the interpretation agreed on by the European Medicines Agencies Co-operation on Legal and Legislative Issues (Emacolex), which consists of officials working on legal issues in the Member States, the European Commission and the Agency.
(33)
65.
Although neither the Commission’s guidelines
(34) nor the view of Emacolex is binding, it is none the less in my view significant that both those bodies, which are active in the field of pharmaceutical regulation, have arrived at the same interpretation.
66.
I do not consider that in practice the above interpretation would enable the manufacturer of a branded product to prevent generic manufacturers from using the abridged procedure by withdrawing that product from the market, a consequence stressed by several of the parties submitting observations.
Even if a particular product to which reference could otherwise be made under point 8(a)(iii) has been withdrawn from the market in a Member State, a generic company will in many cases still be able to obtain authorisation to market the generic product in that State.
If a variant of the reference product is marketed in the Member State in question, the Court's decision in
Generics (35) will often mean that reference can be made to the newer version, even if its authorisation was obtained within the 6 or 10 year period of data protection.
As I argue in my Opinion delivered today in
Novartis
,
(36) such reference may be made whenever a variant product differs from its original as regards its pharmaceutical form, dose or therapeutic use.
The second question
67.
By its second question the referring court asks in effect whether the term ‘marketed’ in point 8(a)(iii) means simply that the reference product has been the subject of a marketing authorisation or whether evidence of actual marketing is required.
68.
With the exception of the EFTA Surveillance Authority, which does not explicitly address the second question, all the parties submitting observations are in agreement that the reference product is ‘marketed’ within the meaning of point 8(a)(iii) if it has been the subject of a marketing authorisation.
69.
I agree with that view.
70.
First, as essentially submitted by AstraZeneca, Generics, the Danish, Netherlands and Norwegian Governments and the Commission, the safeguarding of public health, which is the primary purpose of Directive 65/65,
(37) is ensured not by evidence that the reference product is in fact traded but by the comprehensive particulars and documents provided by the applicant for authorisation to market that product pursuant to the third paragraph of Article 4 of Directive 65/65.
Those particulars and documents, updated by that applicant in accordance with the Annex to Directive 75/318,
(38) remain available to the competent authority for the Member State where the application for the generic authorisation is made.
71.
Second, as the Netherlands Government submits, that criterion has the merit of being easy to apply, whereas it may be difficult to establish whether a product is actually marketed or not, even if it were possible to agree on a definition:
for example, should preliminary advertising, the acceptance of orders or the delivery of products constitute marketing in fact?
72.
Third, as AstraZeneca, the Danish and Netherlands Governments and the Commission submit, that interpretation is consistent with the Commission’s ‘Notice to Applicants’, which states:
‘“Marketing” must be understood as “authorised” as the medicinal product has been authorised under a “marketing authorisation”.’
73.
Finally, that interpretation does not entail the risk alluded to by the Netherlands Government, the Commission and the EFTA Surveillance Authority that a generic authorisation may be granted where a marketing authorisation subsists for a reference product which has in fact been withdrawn from the market for health reasons.
Article 33(2) of Directive 75/319
(39) requires the person responsible for marketing a medicinal product to notify the Member States concerned of any action taken by him to withdraw a product from the market together with the reasons for that withdrawal if it relates to the efficacy of the product or the protection of public health while the first paragraph of Article 11 of Directive 65/65
(40) obliges the competent authority to suspend or revoke an authorisation where the product proves to be harmful in the normal conditions of use or where its therapeutic efficacy is lacking.
Consequently a marketing authorisation should not subsist for a reference product which has been withdrawn from the market for public health reasons.
Conclusion
74.
I am accordingly of the opinion that the questions referred by the Østre Landsret should be answered as follows:
In order to benefit from the abridged procedure provided by point 8(a)(iii) of the third paragraph of Article 4 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, an applicant for a marketing authorisation must demonstrate that at the time of the application the reference product has a valid marketing authorisation in the Member State for which the application is made.
(1) .
(2)
OJ, English Special Edition 1965-1966, p. 20, as amended in particular by Council Directive 87/21/EEC of 22 December 1986, OJ 1987 L 15, p. 36, Council Directive 89/341/EEC of 3 May 1989, OJ 1989 L 142, p. 11, and Council Directive 93/39/EEC of 14 June 1993, OJ 1993 L 214, p. 22.
The legislation has with effect from 18 December 2001 been codified and consolidated in 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, OJ 2001 L 311, p. 67.
However, the relevant provisions have not been amended in their substance.
(3)
Originally the second paragraph, becoming the third paragraph in consequence of an amendment made by Directive 93/39, cited in note 2.
(4)
First and second recitals.
(5)
OJ 1993 L 214, p. 1.
Community marketing authorisations are not at issue in the present case.
(6)
Cited in note 2.
(7)
Second and fourth recitals.
(8)
Point 4 of that paragraph refers to a brief description of the method of preparation and point 7 to a description of the control methods employed by the manufacturer.
(9)
Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of Member States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of medicinal products, OJ 1975 L 147, p. 1.
(10)
As modified by Commission Directive 91/507/EEC of 19 July 1991, OJ 1991 L 270, p. 32.
(11)
Second Council Directive of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products, OJ 1975 L 147, p. 13, as amended in particular by Directives 89/341 and 93/39, both cited in note 2.
Articles 29a to 29h of Directive 75/319 have been amended with effect from 30 June 2000 by Commission Directive 2000/38/EC of 5 June 2000, OJ 2000 L 139, p. 28, which further strengthens the phamaracovigilance obligations imposed.
(12)
Case C-368/96 [1998] ECR I-7967.
(13)
Question 1a, which read
'(a) at the time of the application has been marketed in the Member State for which the application is made', has been withdrawn by the national court.
(14)
Cited in note 11.
(15)
Set out in paragraph 8 above.
(16)
Cited in note 2.
(17)
Cited in note 5.
(18)
Cited in note 2.
(19)
'wenn er … nachweisen kann ... daß die Arzneispezialität im wesentlichen einem Erzeugnis gleicht, das ... in dem Mitgliedstaat, in dem der Antrag gestellt wird, in Verkehr gebracht ist' and
's'il peut démontrer ... que la spécialité pharmaceutique est essentiellement similaire à un produit ... commercialisé dans l'Etat membre concerné par la demande'.
The majority of the other language versions are similarly structured.
(20)
Set out in paragraph 16 above.
(21)
Set out in paragraph 10 above.
(22)
See the first recital in the preamble to Directive 65/65, set out in paragraph 4 above.
(23)
Set out in paragraph 16 above.
(24)
Set out in paragraph 16 above.
(25)
Article 29e of Directive 75/319, set out in paragraph 16 above.
(26)
Article 29f of Directive 75/319, set out in paragraph 16 above.
(27)
See the case-law summarised in Case C-172/00 Ferring Arzneimittel, judgment delivered on 10 September 2002, at paragraphs 19 to 22.
(28)
Cited in note 27, paragraphs 36 and 38 of the judgment, citing Case C-94/98 Rhône-Poulenc Rorer and May
& Baker [1999] ECR I-8789, paragraph 46.
(29)
Set out in paragraph 8 above.
(30)
Cited in note 5.
(31)
November 2002.
(32)
Paragraph 4.2.4 of chapter 1, emphasis in original.
(33)
Point 9.2 of the minutes of the 12th meeting of Emacolex in Helsinki in November 1999.
(34)
It may however be noted that the Annex to Directive 75/318, cited in note 9, as modified by Directive 91/507, cited in note 10, requires the presentation of the particulars and documents accompanying an application for marketing authorisation pursuant to Article 4 of Directive 65/65 to take account of the guidance published by the Commission in its Rules.
The Court moreover referred to the Rules in the context of interpreting another aspect of point 8(a)(iii) in Generics, cited in note 12, paragraphs 31 and 32 of the judgment.
(35)
Cited in note 12.
(36)
Case C-106/01 Novartis Pharmaceuticals UK.
(37)
See the first recital in the preamble, set out in paragraph 4 above.
(38)
See paragraphs 14 and 15 above.
(39)
Set out in paragraph 16 above.
(40)
Set out in paragraph 12 above.