European Union: EU Pharmaceutical Review - Life Sciences

In February we reported that agreement had been reached on the likely final form of the revision to the medicinal products Directive. Directive 2004/27/EC (the "New Directive") amends Directive 2001/83/EC (the unamended text is referred to here as the "Old Directive"). The New Directive was published in the Official Journal of the European Union on 30 April 2004 and Member States have to amend their national laws to ensure compliance by 30 October 2005.¹

Uncertainties about the effect of the Old Directive in relation to applications under the abridged procedure to obtain authorisation for generic products spawned the Generics² and recent Cyclosporin³ cases. This article considers whether the New Directive has clarified how these and similar difficulties will now be addressed.

The New Directive provides an "abridged procedure" which is very similar to that in the Old Directive. Under the Old Directive, a generic competitor could obtain marketing authorisation for his product where:

1. the data exclusivity period in relation to the reference product had expired; and
2. he could show that his generic product was "essentially similar" to the reference product.

This is one form of the so-called "abridged procedure". In broad terms this type of arrangement remains under the New Directive. However, instead of having to show his product is essentially similar, the generic producer will now need to demonstrate that his product is a "generic medicinal product" which is defined for the first time. The application of the definition of "generic medicinal product", as with the test of essential similarity, is likely to be a contentious area. Further, it is not clear that the new "generic medicinal product" test deals effectively with the ambiguities which led to the disputes in the Generics and Cyclosporin cases.

The Generics case enunciated a definition for "essential similarity" as follows: "…a medicinal product is essentially similar to an original medicinal product when it satisfies the criteria of having the same qualitative and quantitative composition in terms of active principles, of having the same pharmaceutical form, and of being bioequivalent unless it is apparent in the light of scientific knowledge that it differs from the original product as regards safety or efficacy". On the basis of this definition, the European Court of Justice ("ECJ") held that data submitted by the innovator to obtain marketing authorisation for new indications could be relied upon by a generic applicant without having to wait for the expiry of any period of data exclusivity in respect of the data relating to the new indication.

The definition of "essentially similar" as set out in the Generics case has been incorporated, with additions, into the definition of a "generic medicinal product" in the New Directive. A product is defined in the New Directive as a generic medicinal product when it has "the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies." As with the definition of essential similarity, there is no mention of the indication for which the product is authorised. The absence of a reference to the indication authorised is the textual basis for the ECJ's decision in Generics. Accordingly, it seems the answer to the question posed in Generics will not change under the New Directive - there will be no automatic data exclusivity for data submitted to obtain marketing authorisation for additional indications. However, the New Directive does offer something additional for new indications: a further year of data exclusivity will be available for new indications which offer "significant clinical benefit ".

The Cyclosporin case is reviewed in detail in the article, ECJ Decides on Protection for Drug Dose and Formulation Types (see "Next Page" link provided at the bottom of this article). In brief, the ECJ considered whether a separate period of data exclusivity existed in relation to the data required to obtain authorisation for new formulations or doses of existing drugs under the Old Directive. The ECJ decided in the Cyclosporin case that data required to be submitted by an innovator company to obtain marketing authorisation for its new formulation could be relied upon by a competitor even where the data for that new formulation was less than 6/10 years old⁴. The ECJ ruled that this would be the case even where the later authorised product had a different formulation or dose to that originally authorised and so could not be said to be essentially similar⁵ to the originally authorised product.

The New Directive's definition of generic medicinal product states: "The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form." The three formulation types in the Cyclosporin case were immediate release oral formulations. Under this new definition, all three of the Cyclosporin forms would be considered as the same "pharmaceutical form". No period of data exclusivity should therefore result from the fact of a change of pharmaceutical form alone, which is one ambiguity from the essential similarity test which has been dealt with by the New Directive.

What the New Directive does not address is the position in relation to other formulation variants outside the scope of immediate-release oral pharmaceutical forms. For instance, will variations in formulations for administration by other routes or controlled release oral formulations be outside the definition of generic medicinal products and will the data in relation to them attract data exclusivity? There seems little doubt that such changes in formulation are outside the definition of generic medicinal product. However, for the ECJ that may make little difference. In the Cyclosporin case, the ECJ decided that differences in pharmaceutical form, whilst an express requirement of the essential similarity test, could be ignored for the purposes of authorising generic products.

The definition of generic medicinal product retains the requirement that the generic product should have the same quantitative composition to be considered a "generic medicinal product". A different dose means that the product would not have the same quantitative composition and so could not be a "generic medicinal product". For a different dose of an authorised product to be considered a generic medicinal product, the requirement in relation to quantitative composition would have to be ignored. In the Cyclosporin case, however, the ECJ held that it was appropriate to ignore a difference in quantitative composition when considering authorisation of a generic product. Whilst it may be predictable that the ECJ would do as it did in the Cyclosporin case and ignore the "quantitative composition" requirement when considering authorisation of generic products under the New Directive, the New Directive does not deal with the point expressly.

The New Directive deals expressly with variations to the active ingredient itself. The definition of generic medicinal product provides that "different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy". The suggestion from this wording is that where a variation to the active ingredient has a significant effect on safety or efficacy further data will be required to obtain approval and such variations will be outside the scope of the generic medicinal product definition. Whether a further period of data exclusivity will apply to such data is unclear. If the ECJ's policy, as applied in the Cyclosporin case, continues to prevail, it may be that the Court could consider that even data in relation to changes in the active ingredient which have the required significant effect on efficacy or safety should be freely available for the purposes of authorising generic products.

The final form of the New Directive confirms that the data exclusivity regime has, as expected, been harmonized across the EU and EEA (European Economic Area) as the "8+2+1" rule. That is, the data can be used by an applicant to apply for marketing authorisation for a generic medicinal product eight years after the date the reference product was authorised but cannot market the product until a further two years have elapsed. A further year of exclusivity is granted to new therapeutic indications which are of "significant clinical benefit".

The New Directive appears to offer some improvements for innovators by harmonising the data exclusivity period at the longer end of the unharmonised range and by offering additional protection for further indications. However, in some areas, such as new formulations and doses, ambiguity remains in the New Directive. On the ECJ's current form, these ambiguities could be resolved in favour of generic manufacturers.

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