Norway: Marketing Authorisation For Parallel Imports Of Medicinal Products Upon Introduc

The article discusses the issue of marketing authorisation (MA) for parallel imported medicinal products (MP) in cases where the initially directly imported MP is withdrawn and a new variant of the same product is registered and granted MA.

It is suggested that with ECJ judgment 16 December 1999 in case C- 94/98, Rhone Poulenc Rorer Ltd ( Zimovane), a standard has been set which may be applicable in these instances. The identity requirement has been modified, as the MPs to be compared do not have to be "identical in all respects". The further test is tied to public health considerations. The two MPs must firstly fulfil the basic requirement of having the "same active ingredient and same therapeutic effect" and secondly that the MP in question does not "pose a problem of quality, efficacy or safety".

The Zimovane test has already been applied, possibly for the first time within the EEA, by Asker and Bærum district court , Norway. In its decision 24 January 2000 concerning Losec enterocapsules and Losec MUPS the court rejected a request for a preliminary injunction.

In Sweden the administrative court "Regeringsrätten" is faced with a similar Losec matter. It remains to be seen whether the "Regeringsrätten" will apply the Zimovane test or will want to ask for a further preliminary ruling by the ECJ. It is suggested that this would not be necessary.

The issue of parallel imports of MPs has been the subject of continous debate and numerous court cases, both on the EU, EEA and national levels.

The need to harmonise the rules concerning trade in MPs within the EU/EEA community has been recognised long time ago. This has resulted in secondary legislation being promulgated and implemented in the different national legislations within the EU and EEA. Among this legislation, Directive 65/65EEC of 26 January 1965, concerning i.a. requirements for obtaining MA is central. The directive has been modified several times, latest with Directive 93/39EEC.

As for parallel imports as such, this has not been a subject of harmonised secondary legislation This means that the primary source for establishing conditions for the parallel importers obtaining MA, is to be found in the case law of the European Court of Justice (ECJ) and the European Court of First Instance.(CFI)

However, by its Communication of 6 May 1982, OJ 1982 C 115/5, the Commission sought to sum up its views on parallel imports based on the legal status after the De Peijper-judgement, case 104/75 1976 ECR, 613. Due to later case law, the Communication does not sufficiently reflect the actual legal situation for parallel importers.

The issue to be discussed in the following is the extent of documentation required in order for the parallel importer to obtain a MA when the initially directly imported MP has been withdrawn and a new variant of the same product has been registered and granted MA..

Article 4 of Directive 65/65 requires that comprehensive documentation is filed with the national medicinal authority to obtain MA. As of 1 January 2000 a new system is introduced partly based on mutual recognition and partly with central authorisation, applicable for the whole of the EEA. It is generally accepted that these documentary requirements are only applicable when a MA is sought in connection with the marketing for the first time of the MP in question, cf.. case C- 201/94, Smith & Nephew and Primecrown, ECR 1996 I-5819, paragraph 21.

However, the extent of modification applicable to parallel importers has been the subject of litigation. The Zimovane judgment would seem to go a long way in solving outstanding issues in this regard.

Parallel imports has its legal foundation in EC Article 3 a and c and Article 28 (ex. Article 30) and EEA Articles 8, and 11, concerning free movement of goods, and the prohibition against quantitative import restrictions or measures with equivalent effect. Article 30 ( ex. Article 36 ) and EEA Article 13 provide for derogation in specifically listed instances, e.g. the protection of public health. When the goods to be parallel imported are MPs, it is undisputed that public health considerations are given great weight. Case law so far has demonstrated how these conflicting interests have been evaluated. After the Zimovane judgment, one may assume that a standard concept now has been developed which will be applicable in the future when deciding requirements for documentation and the national authorities' scope of evaluation.

Ever since the De Peijper judgement, it has been established that it is not necessary for national medicinal authorities (NMA) to require a second trader to produce once more particulars of a MP as to effectiveness and safety in situations where the second trader has imported a MP which in every respect is the same or has no differences concerning the therapeutic effect compared to an earlier product assessed by the NMA, cf.. paragraphs 21 and 36.

In De Peijper it was also clearly stated that the provisions for obtaining a MA stipulated in Directive 65/65, could not expand the scope of derogation set fourth in EC Article 36 (now Article 30)/EEA Article 13, cf. paragraph 31. This means that even if the requirement of obtaining a MA stipulated in Directive 65/65 also is applicable to parallel importers, the conditions for obtaining such MA would have to be modified with due regard to the rules on free movement of goods, EC Article 28(ex Article 30)/EEA Article 11 and considerations of public health EC Article 30 (ex Article 36)/EEA Article 13.

However, a new situation occurred when the initially directly imported MP was withdrawn and a new variant of the same product was registered and granted MA. This gave rise to the Zimovane case.

Based on the Commission notice of 1982, the direct importer alleged that the mere fact that the previous MA had been withdrawn, would have as a consequence that the MA for the parallel importer also had to be cancelled as the parallel importer's MA no longer could rely on the MA for the MP both in the exporting and importing state, cf. paragraph 31. In the Zimovane matter, UK NMA did grant the parallel importer MA based on the direct importer's MA for the new variant of the product, cf. paragraphs 39, and 18. This was not an issue in the case.

The ECJ addressed the considerations to be made by MA's when evaluating the conditions for parallel importers for obtaining MA based on a variant of an earlier registered MP.

In the Zimovane judgment, the ECJ found a solution to this question focusing on free movement of goods and public health considerations, even introducing public health considerations in the similarity or identity test.

"Zimovane" is used in treating insomnia. A new version of Zimovane was developed containing the same active substances and with the same therapeutic effect as the earlier variant. However, the production process and the excipients used were different from the earlier product. Several MAs had been issued to parallel importers regarding the earlier Zimovane. Upon withdrawal of registration for the earlier product, the parallel importers were allowed to apply for continuation of their MA based on a new reference product. UK NMA concluded that the earlier issued MA's for the parallel importers were still valid, using MA for the new Zimovane variant as reference product. Subsequently UK NMA has issued new MA's for parallel importers of the earlier Zimovane variant, based on the MA for the new Zimovane variant.

The new variant of Zimovane was only introduced on the UK marked, whereas the earlier variant was still available on the other national markets within EC/EEA.

The ECJ made reference to the De Peijper and the Smith & Nephew and Primecrown cases and found, based on this case law, that the basic requirements of the identity or similarity test was fulfilled. This meant in the matter at hand that the two variants of Zimovane contained the same active substances, had the same therapeutic effects and common origin.

In its further analyses the ECJ stressed that it follows from EC Article 30 (now Article 28) and Article 36 (now Article 30) that MAs may not hinder parallel imports by requiring that the parallel importer is to fulfil the same conditions as applicants who for the first time seek a MA for a MP, provided it does not entail a danger to the protection of public health. The ECJ also stressed that lesser requirements for the parallel importer as for documentation could not have as a consequence a relaxation of the protection of public health, cf. paragraph 40.

In its further analyses, the ECJ commented on the fact that differences in the excipients may entail differences in the level of security. This is due to the fact that changes in the MP's formulation with regard to its excipients may influence the shelf life of the MP and the bioavailability of the product, cf. paragraph 43. However, even such potential differences should not exclude the possibility for NMAs to use simplified procedure for granting MA's to parallel importers, cf. paragraph 44.

The decisive test is indicated in paragraph 45 which reads:

Firstly, note the obligation on part of the NMAs, they are "required" to authorise. Secondly, that the parallel imported MA does not have to be "identical in all respects" to the MA already authorised. Thirdly, that the basic criteria of "same active ingredient and same therapeutic effect" has to be fulfilled. And fourthly, that the MP does not "pose a problem of quality, efficacy or safety".

From the direct importer it was further alleged that the pharmacovigilance would not function in a situation where the duty to report information on the earlier variant no longer was on the direct importer who had withdrawn its registration on the older variant. The ECJ did not see this as a problem given the existing rules on co-operation between NMA's in the different member states, based on the requirements in Directive EEC 75/319 and later amendments. It was also stated that the holder of a MA in the import state and which belongs to the group holding MA for the earlier variant in other national markets, may be compelled to produce the necessary information, cf. paragraph 46.

It should be added that as from 1 January 2000 the mutual co-operation between NMAs has been brought forward within the EEA concerning i.a. access to documents and data. Additionally, within the framework of WHO, a database available for all national health authorities has been set up in order to report e.g. possible detrimental effects of MPs.

The final argument brought forward by the direct importers was that the beneficial public health effects of the new variant of Zimovane, could not be achieved in a situation where the two variants of the Zimovane pill were on the market simultaneously.

The ECJ also rejected this argument mainly directing the NMA's to make an assessment whether the earlier variant of the imported MP under normal conditions of use does represent any risk as regards quality, efficacy or safety, cf. paragraph 47. If the parallel imported MP does not pose such risks, the modified rules regarding documentation for parallel imports are to be applied.

The judgment represents a further step in the legal clarification as far as the rules for documentation required for obtaining MA's for parallel imported MPs are concerned. In my opinion, the reasoning of the ECJ, in particular paragraphs 40 and 45, are worded in such broad terms that the judgment will be applicable also in instances where the difference between the earlier and new variant do not refer solely to differences of excipients or production process but differences of form, e.g. tablets instead of pills, replacement of the active substance by a different salt or other changes which according to Commission Regulation 541/95 EC, Annex II would require a new application for MA.

On 24 January 2000 Asker and Bærum district court denied a request for a preliminary injunction against continued sale of Losec enterocapsules. The rejection was based on the test in the Zimovane judgment.

AstraZeneca AS (AZ)was for several years and until December 1998 direct importer to Norway of Losecentero capsules. Losec, with the active substance Omeprazol, is used in treatment of overproduction of gastric acid, gastric ulcer and inflammation of aesophageus. In December 1998 AZ withdrew the enterocapsules and introduced instead Losec MUPS. The main differences between enterocapsules and MUPS are: Difference of form; MUPS being in the form of tablets, not capsules. The chemical form of the active ingredient is also different, being magnesium salt (omeprazolmagnesium) for MUPS and omeprazol for capsules. Furthermore, there are differences in excipients as the MUPS do not contain lactose and gelatine. Finally the production process is different.

AZ filed a request for an injunction with the court as the result of the Norwegian MA granting two parallel importers, Paranova AS and Farmagon AS MA's for continued parallel import of Losec enterocapsules, based on the MA for Losec MUPS.

Losec, which is the second most sold MP on the Norwegian market, is one of the most selling drugs within the EU/EEA. The Losec enterocapsules are still available on 11 national markets within the EEA and with coexistence with Losec MUPS on the UK, Swedish and Norwegian markets.

AZ argued that the Zimovane judgment was not applicable in the Losec matter, primarily because of the more extensive differences between the variants of Losec, compared to the variants of Zimovane. The differences between the variants, both in the De Peijper case as well as the Zimovane case, only qualified as "TYPE 1 changes" as stated in Commission Regulation 541/95 EEC, comprising the least important changes. As to the differences in the Losec matter it was alleged that these qualified as" Annex II changes" which require a new application for MA. In this connection it was referred to the fact that when AZ applied for MA for Losec MUPS the required application with comprehensive documentation was produced. The pharmacovigilance aspects, based on the fact that AZ no longer could provide the Norwegian MA with updated information on Losec enterocapsules, was argued, as well as public health arguments. The latter referred to alleged problems for patients experiencing the coexistence of Losec enterocapsules and MUPS. In particular it was referred to the fact that the tablets were developed in order to help patients with problems swallowing.

In rejecting AZ's request, the court established that EEA Article 11 and Article 13 and Directive 65/665 EEC had duly been incorporated into Norwegian law, partly by the EEA Act of 27 November 1992 and partly by Regulation on Pharmaceutical Proprietary Products of 22 October 1993 with later modifications and Regulation 22 December 1999 concerning Medicinal Products. With reference i.a. to the preamble of the EEA Agreement of 2 May 1992 stating the purpose of establishing a homogenous legal area with uniform interpretation and application of the Agreement and secondary legislation, required that not only ECJ practice prior to the signing of the agreement, see EEA Article 6, but also subsequent judgments were to be applied by Norwegian courts.

The court found that earlier ECJ case-law had established that parallel imports would be possible even if the identical reference product had been withdrawn from the market in question, but still was marketed in one or more other countries. The court found that the Zimovane judgment was applicable also in the case at hand concerning Losec. Analysing De Peijper, Smith & Nephew and Primecrown and Zimovane judgments the court concluded that there was no grounds for assuming that particular types of differences between MPs could be decisive as for the granting of MA for parallel importers. It was pointed out that similarity in excipients was not mentioned as a condition in the Smith & Nephew and Primecrown judgment, whereas in the Zimovane judgement it was referred to that the difference in excipients might have an impact on security, even if active substance and therapeutic effects were the same. In Smith & Nephew and Primecrown the similarity in process was set as a condition for parallel import, whereas the Zimovane judgment accepts differences in the processing of MPs.

When evaluating the differences between Losec enterocapsules and Losec MUPS the court found that there was similarity in active substance, similarity in therapeutic effect and bio- equivalence. Based on evidence presented to the court, the court found that difference of form in general would have limited effect on public health and in particular this was the case with the Losec enterocapsules. As for difference in the chemical form of the active ingredient, this was not found to have any appreciable consequences for the patients or public health in general. The same was concluded with regard to different excipients and different production processes.

AZ's reference to public health grounds and pharmacovigilance concerns were also rejected with reference to the Zimovane judgment. The court added that it also based itself on the Norwegian MA's assurance that established co-operation between other national MA's and international data bases secure sufficient supervision.

With direct reference to AZ's argument that the changes in this instance necessitated a full application for a new MA on part of AZ, for MUPS, Annex II Changes, according to Commission Regulation 541/95 EEC, the court did not find this decisive. On the contrary, AZ had through this application documented that there were no differences with regard to security or quality between the capsules and the tablets.

The court's decision rejecting the injunction is now final. However, the underlying main issue is still pending before the same court. Time for an oral hearing has so far not been set. It is, however, interesting to note that probably Asker and Bærum district court has been the first national court within the EEA to apply the principles laid down by the ECJ in the Zimovane judgment.

In Sweden there is also a Losec matter which presently is before the "Regeringsrätten". It will be interesting to see whether "Regeringsrätten", also will apply the Zimovane judgment test or whether the court will find it necessary to address questions for a preliminary ruling from the ECJ. Interestingly enough, the Swedish MA has taken the opposite view compared to the Norwegian MA in the Losec matter, but argued in favour of the ECJ's finding in the Zimovane matter.

In my opinion there is every reason for the "Regeringsrätten" to apply the Zimovane test with the same result as the Norwegian court and that there should be no need for presenting supplementary questions to the ECJ.

9.1 With the Zimovane judgment a standard would seem to have been set which may be applicable regarding MA for parallel imports in all instances where an initially directly imported MP is withdrawn from the market and a new variant of the same product is registered and granted MA. At least this is the case where the initially directly imported M P still is available on one or more national markets within the EU/EEA.

9.2 Following its earlier case - law, the ECJ strikes a balance between the obligation for NMAs to secure free movement of goods as stipulated in EC Article 28(ex Article 30)/EEA Article 11 and the application of the derogation based on considerations of protection of public health, cf. EC Article 30 (ex Article 36)/EEA Article 13.

9.3 The identity or similarity test has been modified, as the parallel imported MP representing the earlier variant of the product does not have to be "identical in all respects" to the MP already authorised, representing the new variant of the product.

9.4 The identity or similarity test is fulfilled when firstly, the two MPs have the "same active ingredient and same therapeutic effect" and secondly, that the MP does not "pose a problem of quality, efficacy or safety".

9.5 With the present system of pharmacovigilance set up according to Council Directive 75/319 EEC, with later amendments, Article 29a) fl. and the existence of i.a. the WHO database for adverse reactions to MPs, the control aspects are considered sufficiently taken care of, in spite of the withdrawal of the initially directly imported MP, at least as long as this product is available at least on one or more national markets within the EU/EEA.

9.6 As probably the first national court in the EEA, Asker and Bærum district court, Norway, in its decision 24 January 2000 has applied the Zimovane test concerning Losec enterocapsules and Losec MUPS, rejecting a request for a preliminary injunction.

9.7 The application by a Norwegian court of a ruling by the ECJ rendered prior to the signing of the EEA Agreement 2 May 1992 is in accordance with the explicit provision of EEA Article 6 and Norwegian implementation legislation by the EEA Act of 27 November 1992. However, the application of an ECJ ruling rendered after that date, as in this case has a more complex bases, due to the formal independence of the Norwegian courts under the EEA Agreement.

9.8 The legal bases is to be found in the preamble of the EEA Agreement "..to arrive at and maintain a uniform interpretation and application of the EEA Agreement and those provisions of the Community legislation which are substantially reproduced in that Agreement.." Furthermore, Article 3.2 of the Agreement establishing a Surveillance Authority (ESA)and a Court of Justice (EFTA-Court)between the EFTA States of 2 May 1992, states that the ESA and the EFTA-Court are to "pay due account" to decisions by the ECJ. The Norwegian Supreme Court has already in a judgment of 12 December 1997, Gerd Eriksen et.al. concerning transfer of undertakings and the Norwegian implementation of Council Directive 77/187 EEC, stated that also rulings by the ECJ after 2 May 1992 have direct importance for "what is Norwegian law in this field" . Consequently, Asker and Bærum district court was well in line with EEA- and Norwegian law when applying the Zimovane test.

This article contains general information on the subject matter and shall not be relied upon for a specific case. Specialist advice should be sought with respect to any specific circumstances.