European Union: ECJ Decides on Protection for Drug Dose and Formulation Types

The European Court of Justice ("ECJ") ruled on 29 April 2004 that, among other things, innovator pharmaceutical companies will not have the benefit of data exclusivity for new formulations or doses of existing drugs. The decision means that generic drug companies will be able to rely upon the clinical and other data generated by innovator pharmaceutical companies to support authorisation of new formulation types and doses without waiting for the data-exclusivity period (up to 10 years) to expire.

The case involved Novartis' immunosuppressant drug containing the active ingredient cyclosporin.¹ Sandoz Pharmaceuticals (UK) Ltd (now Novartis) had originally formulated the product in a macroemulsion form sold under the name Sandimmun. The product in this macroemulsion formulation type was the first cyclosporin product to receive authorisation in the European Union when it was approved in 1983.

Novartis subsequently developed an alternative formulation of cyclosporin, this time in the form of a microemulsion which was designed to overcome some of Sandimmun's difficulties of absorption and administration. This microemulsion product was sold as Neoral and received its first marketing authorisation in the EU in Germany in 1994. Marketing authorisation for Neoral in the UK was granted in 1995.² In January 1999, the generic company SangStat was granted a marketing authorisation by the Medicines Control Agency in the UK ("MCA", since renamed the Medicines and Healthcare Regulatory Agency) for its product containing the active ingredient cyclosporin, this time formulated as a nanodisperion and sold under the name SangCya.

Each of the three products in question is, when administered to the patient, a liquid taken orally and, in each case, contains the same active ingredient, cyclosporin. However, the detailed formulation type in each case is different. The different form of the products when administered means that they are not bioequivalent: they vary in their bioavailability, that is, the rate and extent of their absorption into the body and transfer to the site of action. This is significant because cyclosporin has a narrow therapeutic index. If the patient receives too much or too little of it, it will not be effective and may be detrimental to their health. As a consequence, the actual level of cyclosporin in the blood of a patient has to be monitored and the dosage adjusted as necessary.

In order to obtain its first marketing authorisation for the Sandimmun macroemulsion formulation Sandoz was required to submit a full dossier of data to the regulatory authorities. Novartis was not, however, required to provide a complete new dossier for the new microemulsion formulation type (Neoral) - the active ingredient having already been evaluated in the original Sandimmun application. The application for the Neoral microemulsion formulation was made under the so called "hybrid abridged" procedure (see below).

The case centres around SangStat's ability to rely on the Novartis clinical data filed with the MCA and relating to Neoral to support SangStat's marketing authorisation for its SangCya product. Novartis argued that the data exclusivity (also known as the data protection) regime means that SangStat cannot rely on this data to have its product authorised so that it can be placed on the market.

The marketing authorisation obtained by SangStat was granted under the hybrid abridged procedure. In granting the authorisation, the MCA in the UK relied not only on data submitted by Novartis in respect of the original Sandimmun product but also upon data which Novartis had supplied in support of the microemulsion Neoral formulation. The MCA did not require SangStat to submit its own bridging data equivalent to the data which Novartis had been required to submit for its Neoral formulation.

The legislative framework (Directive 65/65 as amended by 2001/83/EC) provides that where party A already holds an authorisation for a product party B does not have to repeat all the clinical trials carried out by party A to obtain the original authorisation where party B's product is "essentially similar" to party A's product. The only data party B has to submit is data to show that his product is essentially similar. This is an "abridged procedure". Where the later product is to be administered by different routes or in different doses, the products are not considered "essentially similar" and additional pharmacological, toxicological and/or clinical trials are required. This is a "hybrid abridged procedure".

By using either of these abridged procedures, party B avoids the considerable effort and expense involved in carrying out full clinical trials. In recognition of the significant effort and expense incurred by party A in developing the data required to have the products authorised in the first place, a period of "data exclusivity" is afforded to party A. During the period of data exclusivity, no other party may rely upon party A's data without party A's consent. The period of data exclusivity currently varies from Member State to Member State being either six or ten years (as in the UK).

At the time of SangStat's application for a marketing authorisation, the data in relation to the original Sandimmun macroemulsion product was outside the data exclusivity period so could be relied upon by the MCA in granting the authorisation. However, the data in relation to Novartis' Neoral microemulsion formulation was less than ten years old and so within the data exclusivity period of protection.

Novartis argued that the MCA was not therefore entitled to rely upon it to grant the authorisation to SangStat. Novartis also claimed that the MCA was precluded from granting an authorisation based solely on the old Sandimmun macroemulsion data because the nanodispersion formulation of SangCya was not essentially similar to the Sandimmun macroemulsion formulation. Finally, Novartis argued that the MCA's decision infringed the general principle of non-discrimination, insofar as similar situations (in this case, the assessment of Neoral and SangCya) should not be treated differently in terms of the data required for authorisation unless such differentiation is objectively justified.

The ECJ held, among other things, that SangStat could rely upon the data which Novartis had submitted to support its Neoral formulation type even though the data were less than 10 years old. The Court held that SangStat could do so notwithstanding its finding that Neoral and Sandimmun were not "essentially similar".

On a broader level, the ECJ held that in a situation where there is an initial reference product, Product A authorised for longer than the 6/10 years data exclusivity period, (Sandimmun in this case) and a development of the reference product, Product B (Neoral in this case) authorised for less than 6/10 years then a third party can rely upon the data submitted in respect of not only Product A but also Product B in certain circumstances. Interestingly the ECJ seems to have taken the view that the protection of the data relating to Product B would have been an extension to the data exclusivity period in respect of product A rather than a separate period of data exclusivity in respect of the development of Product B.

The generic competitor will be able to rely on the newer data for Product B where Products A and B are:

1. essentially similar; or
2. essentially similar apart from the route of administration; or
3. essentially similar apart from their dose.

The ECJ takes the view that since the factors in (b) and (c) imply that the products are not bioequivalent, reference must also be able to be made to the data for Product B, where Products A and B are only different by their bioavailability even though the rate of administration and dose are the same. In other words, when authorising generic Product C, with reference Product A authorised for more than 6/10 years, an authority can refer, without consent, to data relating to Product B, authorised within the last 6/10 years under the hybrid abridged procedure where those data show Product B is safe, though suprabioavailable to Product A in the same dose.

The judgment also gives some guidance on the meaning of pharmaceutical form. It states that in determining pharmaceutical form account must be taken of the form in which it is presented and the form in which it is administered, including the physical form. In the context of the products discussed in the case which are presented in the form of a solution to be mixed in a drink for administration to the patient and which, after mixing, form, respectively, a macroemulsion, a microemulsion and a nanodispersion, these are to be treated as having the same pharmaceutical form provided that the differences in the form of administration are not significant in scientific terms.

The decision could allow generic versions of new formulations and doses to enter the market years earlier than if data exclusivity had been recognised for revised formulations and doses. It also means that whilst innovator companies will be required to go to the considerable expense of demonstrating to the regulatory bodies the safety and efficacy of new formulations and doses, the data exclusivity will not reward that investment by providing market exclusivity. The situation for doses, and dosing regimes is compounded by the lack of protection afforded by the patent system (as applied in the United Kingdom, at least - see the Taxol decision, BMS v Baker Norton 2001 R.P.C. 1). The ECJ's 29 April 2004 judgment is a further reduction of the incentives for innovator pharmaceutical companies to bring improved formulations and doses to market.

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