This Article appears in the May 2005 issue of Generics Web
Data Protection: High Court allows registration of Alendronate 70mg
High Court judgment
In May the English High Court gave judgment in the action brought by MSD against the MHRA's decision to grant marketing authorisations for alendronate 70mg, a generic version of Fosamax Once Weekly1. APS (Teva), Generics (UK) and Arrow Generics intervened. The MSD Fosamax case is the latest in a long line of cases before national courts and the European Court of Justice in which the balance of interest between innovators and generic pharmaceutical companies, and the meaning of Directive 2001/83/EC ("the Directive") and its precursors have been considered.
The Directive has been amended by Directive 2004/27/EC, which should be implemented by October 2005. Nevertheless, the decision is important for current and past registrations, and as an indication of the way in which the courts think.
The recitals to the Directive provide "………experience has shown that it is advisable to stipulate more precisely the cases in which results of pharmacological and toxicological tests or clinical trials do not have to be provided with a view to obtaining authorisation for a proprietary medicinal product which is essentially similar to an authorised product, whilst 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 overriding cause."
Article 8 of the Directive provides that applications for marketing authorisations have to include the following:
- (c) Qualitative and quantitative particulars of all the constituents of the medical product in usual terminology,….
- (f) Posology, pharmaeceutical form, method and route of administration and expected shelf life…
- (i) Results of:
- physico-chemical, biological or microbiological tests,
- toxicological and pharmacological tests,
- clinical trials.
Article 10 sets out the "essential similarity" derogation from this requirement. It provides that an applicant is not required to provide results of toxicological and pharmacological tests or the results of clinical trials if he can demonstrate "that the medicinal product is essentially similar to a medicinal product which has been authorized within the Community, in accordance with Community provisions in force, for not less than [six/ten] years and is marketed in a Member State for which the application is made.
However, where the medicinal product is intended for a different therapeutic use from that of the other medicinal products marketed or is to be administered by different routes or in different doses, the results of appropriate toxicological and pharmacological tests and/or of appropriate clinical trials must be provided"
It is this derogation which forms the basis of abridged applications for generic pharmaceutical products. The proviso for the derogation to Article 8(3)(i) applies in situations where products are not essentially similar: where the product for which authorisation is sought differs from the product which has been authorised for ten/six years only in particular respects. In certain cases, the applicant may rely upon the original data and submit additional "bridging" data to cover respects in which there is a difference. This procedure is called the "hybrid abridged procedure".
MSD: FOSAMAX: The Background.
Fosamax 5mg was authorised in the EU in 1993, Fosamax 10mg in May 1995 and Fosamax Once Weekly in November 2000. MSD's formulation patents on Fosamax were revoked in the UK in January 2003 and in Europe in August 2004. Teva, Generics and Arrow wanted approval for alendronate 70mg, the once weekly preparation. Could the MHRA grant licenses to them for this form under the abridged procedure, even though it had not been marketed in the UK for ten years? MSD claimed that the matter had not been determined by previous cases and that there should be a reference to the ECJ.
The ECJ has given judgment in three cases relating to the derogation to 8(3)(i). These are the "Generics" case2 , (new indication), the "Novartis"case3 (Supra-bioavailability - no essential similarity) and the "APS" case4 (different pharmaceutical form). None of these cases explicitly considered posology (the schedule of dosage: how much and how often a particular dose of medicine should be taken). This, argued MSD, was an issue which had been left open by the ECJ and should be determined by it. The MHRA and intervening generic companies argued that this matter had already been decided, and in order to evaluate whether that was the case, the court considered previous case law.
GenericsThe Generics case concerned the grant of a licence for a product for a new indication for which the innovator's product had been licensed for less than 10 years. The product had been marketed for more than 10 years for other indications.
The ECJ concluded that:
"a medicinal product is essentially similar to an original medicinal product where it satisfies the criteria of having the same quantitative composition in terms of active principles, of having the same pharmaceutical form and of being bio-equivalent, unless it is apparent in the light of scientific knowledge that it differs significantly from the original product as regards safety or efficacy."
"A medicinal product that is essentially similar to a product which has been authorised for not less than [6/10] years in the Community and is marketed in the Member State for which the application is made may be authorised, under the abridged procedure…for all therapeutic indications already authorised for that product".
Finally, in relation to new dosage forms and the like the ECJ held that:
"A medicinal product that is essentially similar to a product which has been authorised for not less that [6/10] years in the Community and is marketed in the Member State for which the application is made may be authorised, under the abridged procedure…for all dosage forms, doses and dosage schedules already authorised for that product".
The Generics case established that the regulatory authorities could, for an essentially similar product, refer to an innovator's data when considering a generic manufacturer's application for a marketing authorisation; and, the generic authorisation could cover all of the indications and dosage forms licensed to the innovator as at the date upon which the generic company submitted its application. The case is important not only because the court defined what is meant by "essential similarity" but also because it shows how the court reconciled the conflicting interest of innovators and generic companies. In particular, it shows the absence of any weight to be given to expenditure and time and costs by innovators in developing their product. It also explains the importance of protection afforded to innovators by Intellectual Property Law to which the data protection given by Article 10 is only an addition.
The decision in Generics left open the question of whether an applicant could rely on data supplied by an innovator where the generic product C was not essentially similar to the original product (A) but was essentially similar to a development of that product, product B. Novartis had developed an original product "A", Sandimmune, into another product, Neoral, which was not bio-equivalent to Sandimmune.
Generic companies sought authorisation for a product which was essentially similar to Neoral. The court ruled that although bioavailability was not explicitly referred to within the proviso, it was implicit. The generic applicant could rely on the bridging data on which the innovator had relied in relation to Neoral, and the original data in relation to Sandimmune. It was accepted that the products were not essentially similar, and stated that the purpose of the proviso was to allow applicants whose product differed from an existing product in the ways stipulated by the proviso to submit only bridging date.
APS also related to an application for a product which was not in the pharmaceutical form of the original product A, but in the form of the development, product B. Prozac had been authorised in capsule form for more than ten years, and APS sought to market a liquid form of the drug, Fluoxetine, liquid Prozac having been marketed for less than ten years. The court applied the same logic as in Novartis. In other words, it determined that pharmaceutical form, whilst not referred to in the proviso, was implicit within it.
There was an additional argument in APS. It was argued that the generic applicant must apply under the proviso, but the Advocate General and court stated that this was not
necessary. The Advocate General concluded that:
"There are good reasons against requiring an application in respect of product C to proceed under the proviso. The proviso operates in circumstances where bridging data are required because of a difference between the new product and the earlier product or products to whose data reference is made. Where product C claims essential similarity to product B which is a variant of product A, no addition data are required. There is therefore no need to proceed under the proviso".
MSD sought a reference to the ECJ, on the basis that the question at issue was unresolved. It relied on three distinctions from previous decisions: " The difference between MSD's original product (Fosamax 5mg and 10mg "A") and the development (Fosamax once weekly 70mg "B") was one of posology, a difference that had not been the subject of previous decisions. " Fosamax Once Weekly involved had multiple differences from the reference product A (strength and bioavailability). " MSD had received authorisation for Fosamax Once Weekly following a full "stand alone" application, not an application under the hybrid abridged procedure - it did not rely on bridging data, and hence the generic applicants should not be entitled to do so.
There was a more fundamental argument, namely that there was no statutory rule for allowing registration through the abridged procedure of products which were not essentially similar. In other words, the whole basis of the ECJ's caselaw concerning the proviso was wrong.
The Judge decided that changes in bioavailability were implicit in Novartis. A change in route of administration generally entails different bioavailabilities. Arguably, posology is included in the proviso ("different doses"). However, the Judge felt that even if the word "dose" was given a restricted meaning of strength, a change in posology fell implicitly within the proviso: a change in dose generally entails a change in posology.
The Judge considered that it would undermine the purpose of Article 10 to provide a further period of protection merely because the innovator had changed the frequency with which doses should be taken by increasing strength. In relation to the second point, it was clear that the fact that Fosamax Once Weekly differed in more than one respect from Fosamax 5mg and 10mg did not take it out of the proviso.
Finally, he stated that it would be wrong if an innovator could acquire a further period of protection merely because the authority had sanctioned a full, as opposed to hybrid abridged, applications. Generic companies could not influence the manner in which innovators applied for product licenses on their developments.
The Judge concluded that generic companies could not be required to provide further data under the proviso where their product was essentially similar to the innovator's product B, (the development). Any other construction would not achieve the objective of the recitals of avoiding unnecessary repetitive tests. The only purpose would be to give a further period of protection to innovators - but they were already protected by Intellectual Property Rights, and by Article 10.
Finally, the Judge rejected MSD's submissions that the previous ECJ decisions were wrong, in that the proviso only applied where the generic product is essentially similar to the original product. That argument had been made in Novartis, and had failed. Such construction would not achieve the primary purpose of the Directive. Rather, it was inconsistent with the Directive. If the generic product was essentially similar to a development, i.e. was no less safe or efficacious from the development, the only purpose to be achieved by giving the further period of protection was to protect the innovator.
The Judge's conclusions as to whether a reference could be made under the proviso to original products and/or developed products are interesting. Applying a purposive approach, it does not matter whether an application is regarded as being under Article 10(1)(a)(iii) or under the proviso. In either case, and the matter to be determined as to whether further tests have to be carried out, and whether or not the product is essentially similar. That is the construction which is required in order to achieve the objectives of the Directive.
To an English lawyer, these comments are interesting. English Law required literal construction, and the intention of legislators was irrelevant. However, European Law (and English Law based on European Law) requires purposive construction. In other words, the purposes of the legislator, the philosophy behind the legislation, are to be taken into account in determining meaning. Hence, it does not really matter whether an application is made under the proviso or not: what is important is that the purpose of the legislator as expressed in the recitals is followed.
Reviewing the case law, the Judge decided that the principles enunciated by the court in Generics, Novartis and APS applied. There was nothing further to be determined by the European Court and a reference was refused. The ECJ had not specifically considered a change in posology before, but the ECJ had considered the principles by which the Treaty was to be interpreted, and the domestic court had to apply these. The MSD case raised no new issues of principle.
No doubt the matter will be appealed. In my view, the decision is correct and a reference should not be allowed. We can expect, however, that tension between the interests of innovators and generic companies will continue.
Anna McKay, June 2005
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