Two recent cases in the European Court of Justice (ECJ) have further eroded the principle of data exclusivity by limiting the extent to which proprietary pharmaceutical companies may rely on the protection afforded to their regulatory data beyond the initial period of protection provided for newly authorised medicines. The focus of the cases was the "essential similarity" of the generic medicine with the proprietary medicine in question.
In the first case, Eli Lilly, which markets the anti-depressant, Prozac, in both capsule and liquid formulation, was unsuccessful in preventing Approved Prescription Services gaining a marketing authorisation in respect of a liquid formulation of a similar product, by reference to Eli Lilly's data on Prozac liquid which had not yet been on the market for ten years.
The second case concerned SmithKline Beecham's challenge of a Danish decision to grant Synthon a marketing authorisation for paroxetine mesylate on the basis that Synthon could rely in part on data as to safety and efficacy filed in support of SKB's authorisation for paroxetine hydrochloride. The Court held that two products with the same therapeutic moiety, but differing as to the identity of the salt that is combined with that therapeutic moiety, should be regarded as essentially similar. Synthon could therefore rely on regulatory data submitted by SKB once the data exclusivity period had expired.
These cases follow the defeat suffered by Novartis in April 2004, when it failed to prevent cross-referencing of its data on its immuno-suppressant drug, by a generic manufacturer.
In order to market a medicine in the EU, a marketing authorisation ("MA") must first be obtained. Authorisation will only be granted if data is provided which supports the safety and efficacy of the medicine. The legislation provides for an abridged procedure for obtaining a MA, whereby an applicant shows that the second medicinal product is "essentially similar to a product authorised in the country concerned" and does not have to produce the toxicological, pharmacological or clinical data to obtain authorisation for the second product. For this procedure, the applicant must have the consent of the person who provided the original data or an appropriate period of time (6-10 years) must have elapsed following original authorisation (referred to as the data exclusivity period). Where the medicinal product is intended for a different therapeutic use from the reference product or administered by different routes or in different doses, the applicant must provide appropriate pharmacological, toxicological or clinical data (which is referred to as the hybrid abridged procedure).
In the Novartis case, Novartis had developed a drug called Sandimmun, containing the active ingredient, cyclosporin, for which an MA was granted in 1983. Novartis subsequently developed a newer formulation of the drug, called Neoral. SangStat developed a cyclosporin-based medicine called SangCya and applied for market authorisation under the abridged procedure, with Sandimmun as the reference product. SangStat provided evidence to show the essential similarity between the products, and also showing bioequivalence between SangCya and Neoral. While Sandimmun had been authorised for more than 10 years (the data exclusivity period in the UK), Neoral had not. However, the UK's regulatory authority, MHRA, granted the authorisations relying on data provided by Novartis in support of its abridged application for MA for Neoral. Novartis appealed to the Court of Appeal who referred the matter to the ECJ.
The ECJ held that, in considering an application for MA under the abridged procedure for a new product, a Member State's competent authority is entitled to refer, without the consent of the person responsible for marketing, to data submitted in support of a variant of the reference product even though that variant had been authorised for less than the data exclusivity period where that data consisted of clinical trials provided in order to demonstrate that the variant, though suprabioavailable to the reference product when administered in the same dose, was safe. i.e. the MHRA was entitled to refer to the Neoral data even though the product had been authorised for less than 10 years.
This followed from its conclusion that, if an applicant is entitled under the hybrid abridged procedure to refer to the data relating to a variant which differs from the reference product in the route of its administration or dose, since the differences in those two factors generally imply that the variant and the reference product are not bioequivalent, that applicant must likewise be entitled to do so where the two products are distinguishable only by their different bioavailability, even though the route of administration and dose remain unchanged.
The Court rejected arguments that a reference was only permitted when the products were essentially similar because it would have the effect, in practice, of limiting the abridged procedure only to new therapeutic indications of the reference product i.e. products having the same qualitative and quantitative composition in terms of active principles, the same pharmaceutical form and bioequivalence.
The Court concluded that an application may be made under the proviso (hybrid abridged procedure) provided the medicinal product is essentially similar to the authorised product, unless one or more of the differences set out in the proviso apply. Applicants for marketing authorisation may refer to the documentation where products resulting from the development of the reference medicinal product and the reference medicinal product are essentially similar, apart from the route of administration or the dose as the case may be.
Eli Lilly case
The more recent case of Eli Lilly (Lilly) involved its liquid formulation of the anti-depressant Prozac (fluoxetine). An MA was granted in 1988 in respect of the drug sold as capsules. In 1992 Lilly was granted an MA for a liquid formulation, under the abridged procedure. In 1999 Approved Prescription Services (APS) applied for a MA under the abridged procedure for a liquid formulation generic product, on the grounds that it was essentially similar to Lilly's liquid Prozac formulation. The MHRA refused this application on the basis that the "essentially similar" product had been approved for less than 10 years. On appeal to the High Court, the court referred to the ECJ.
The ECJ subsequently made reference to the Novartis decision. In the Novartis case, the Court had held that if an applicant is entitled under the proviso to refer to the data relating to a variant product which differs from the reference medicinal product in the route of its administration or dose, since the differences in those two factors generally imply the two products are not bioequivalent, it must also be entitled to do so where the two products are distinguishable only by their different bioavailability, even though the route of administration and dose remain unchanged.
The ECJ considered that the same reasoning could be followed in the Lilly case where the original medicinal product and the variant differ only in that they have a different pharmaceutical form. Since a new route of administration generally entails a change in pharmaceutical form, the situation was considered to be analogous to that in the Novartis case.
In the SKB case, the definition of "essential similarity" was at issue and in particular the aspect of the definition that the two products should have the "same qualitative and quantitative composition in terms of active principles". SKB first obtained its MA for Seroxat (the active substance is paroxetine hydrochloride) in 1993. In 1999 Synthon and Genthon submitted largely identical applications for MAs with the Danish competent authority for paroxetine mesylate, under the abridged procedure citing Seroxat as the reference product. The Danish authority granted the MAs and SKB challenged the decision, on the basis that paroxetine mesylate was not the same "active principle" as paroxetine hydrochloride and therefore there was no essential similarity between them.
The ECJ ruled that Seroxat and the generic medicines were essentially similar for the purposes of the legislation. It held that a medicinal product containing the same therapeutic moiety as the reference product but combined with another salt should be regarded as having the "same qualitative and quantitative composition in terms of active principles". Synthon and Genthon could therefore rely on SKB's Seroxat regulatory data once the relevant period for regulatory data exclusivity for the data submitted by SKB had expired.
These cases demonstrate the continuing movement towards erosion of the value of data exclusivity to the proprietary industry. The new legislation set out in Directive 2004/27/EC is to be implemented in member states by 30 October 2005. The new legislation deals with some of the issues raised in the cases by providing a new definition of "generic medicinal product" including the provision that the 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 regards to safety and/or efficacy. However the case law continues to extend these principles and highlights the diminishing value of data exclusivity, except in relation to original new products.
For further information about the legal aspects of these cases, or to discuss any pharmaceutical issues affecting your business, please contact Zelda Pickup on +44 (0) 20 7367 2043 or by email at [email protected] or Natalie Wood on +44 (0) 20 7367 2523 or by email at [email protected]