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An applicant is not required to provide the results of pre-clinical tests and clinical trials if the product is a generic and the reference product has been authorised for at least eight years in a Member State.
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A generic cannot be placed on the market until ten years from initial authorisation of the reference product.
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The ten year period is extended to eleven years if the original holder of the marketing authorisation obtains a new therapeutic indication which brings a significant clinical benefit in comparison with existing therapies.
If a company wants to apply for a generic product within the first eight years, it must do its own safety and toxicology work, and its own clinical trials (if it can). This is not always possible. There may be ethical reasons against carrying out trials, and of course, costs may be prohibitive for a generic product. After eight years, the regulatory authorities can cross-refer to the innovator’s data on safety and toxicology, and the generic company must wait another two years before it can actually market the product. In other words, the innovator has at least ten years of market protection even if his patent has passed into the public domain.
If an innovator obtains an authorisation for one or more new therapeutic indications which are held to bring a significant clinical benefit in comparison to existing therapies, he is entitled to another year of protection, taking the total to eleven years. It seems that that extra year applies to all indications, including the indications which were initially permitted. The MHRA has said that in its view “significant clinical benefits” require that no product containing the same active substances has previously been authorised in the relevant indication and/or extended to new categories of patients. I am sure there will be argument here! It seems that if a product is used “off label” then formal application later made for that indication, the innovator should not be entitled to the additional one year, but my guess is that innovators will want that extra year in such a case. We shall have to wait and see.
Essentially Similar cf Generic
Before 2004/27 the abridged procedure was available for “essentially similar” products. In 2004/27, instead of descriptions of essential similarity, the abridged procedure is stated to be available for “a generic of a reference medicinal product…”. A “generic medicinal product” is defined as a product which “has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, that is bio-equivalent with the reference medicinal product and has been demonstrated by appropriate bioavailability studies. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance should be considered to be the same active substance, unless it differs significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy…must be supplied by the applicant. The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form. Bioavailability studies need not be required if the applicant can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines.
The definition of a generic product takes into account much of the past ECJ case law. It is on all fours with the Generics, and Novartis cases. However, it does not include all dosage forms of the product and in that respect differs from the Generics case, in which the ECJ decided that “An [essentially similar product] may be authorised under the abridged procedure… for all dosage forms… authorised for that product”.
Hybrid Abridged Procedures
Article 10.3 of the directive states:
"In cases where the medicinal product does not fall within the definition of a generic medicinal product…or where bio-equivalence can not be demonstrated through bioavailability studies, or in case of change of the active substance(s), therapeutic indications, strengths of pharmaceutical form or route of administration, vis a vis the reference medicinal product, the results of the appropriate pre-clinical tests or clinical trial must be provided. "
Does it matter that products that have a different indication, strength, form or route of administration have to be dealt with under this section, rather than being treated as a generic? It is certainly different. Under the earlier legislation, products incorporating these differences might have been regarded as ‘essentially similar’, rather than being considered under the Proviso., European legislation is to be construed purposively, and the purpose of the Directive is to avoid repetitive tests without overriding cause and paragraph 3 requires “appropriate pre-clinical tests or clinical trials”. In some cases, results will simply not be appropriate, and it should not matter whether they are regarded as inappropriate because the product is a generic, essentially similar, or whether it is covered under this section.
At the same time, it does not fit with the words of the Advocate General in APS, when he said “There are good reasons against requiring an application of a product which was essentially similar to a variant of a reference product to proceed under the Proviso. The Proviso operates under circumstances where bridging data are required because of a difference between the new product and the earlier products, 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 additional data were required. There was therefore no need to proceed under the Proviso”.
Reference Product
2004/27 introduces provision for a European reference product. A generic manufacturer can now apply for a marketing authorisation in any Member State and rely on the dossier of information already submitted from the European Reference Product in another Member State. The other Member State must supply all the relevant documentation requested.
Up to now, some regulatory authorities, including the UK, would not supply confidential information on UK reference products: Now, it is obliged to support generic abridged applications in other Member States. There may be more extensive information possessed by the authorities in one country than in the country from which the application is made and a generic company could apply for registration on the basis of the reference product in the country with more extensive information, perhaps enabling it to market a product with different dosages, and broader indications than the innovator’s own product in that country. Essentially, it seems to me that generic companies ought to be able to choose to refer to the most attractive marketing authorisations for their purposes, and to have their registrations reflect the scope of such authorisations.
Bolar Provision
Long after the US adopted its “Bolar” Provision allowing a generic pharmaceutical company to conduct tests on a patentable compound before patent expiry, Directive 2004/27 provides for something similar. Until now, different countries have had different provisions as to the kind of work which might be carried out during patent term. Patent laws contained an “experimental use” exemption, but different countries have different views as to what is permitted under this exemption, and in practice, many companies carried out their clinical trials outside the EC. New Article 10.6 states :
“Conducting the necessary studies and trials…and the consequence of practical requirements should not be regarded as contrary to patent rights or to SPCs for medicinal products”.
National patent laws will have to be amended to take account of 2004/27, and there is no definitive list of the kind of studies and trials or “consequential practical requirements” which fall within exemption. There is a risk that each country will interpret this differently. The UK, and several other countries, has decided to adopt the wording of the Directive as it stands into Patent Law. In the UK, Section 60(5) of the Patents Act 1977 is to be amended so that the Bolar Exemption is added to the list of exemptions. The wording of the statute would thus accurately reflect the Directive – and it would be up to case law to determine exactly what this means.
The UK Patent Office has stated that in its view, the exemption should be interpreted to cover only “abridged” and “hybrid” abridged applications for marketing authorisations in the EEU and these include:
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The manufacture and importation of active substances in sufficient quantities to conduct trials and validate the manufacturing process in accordance with regulatory requirements.
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The development of the final pharmaceutical form of the actual substance.
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The conduct of pre-clinical tests, clinical and bioavailability trials and stability studies.
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The manufacture and supply to the regulatory authorities of samples of active substances, precursors, intermediates, impurities and finished product samples.
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The compilation and submission of a marketing authorisation application or variation application.
The UK Patent Office believes that activities undertaken for purposes other than applying for the marketing authorisation will not be exempted, e.g. tests to see whether the generic company can manufacture to suitable quality. It is not clear whether the subjective intention of the manufacturer is to be taken into account. If a company intends to apply for a marketing authorisation, but changes its mind, will its activities infringe patents or not? The MHRA believes that the Bolar Provision encompasses aborted development.
Where can we expect conflict in future cases?
• Hybrid Abridged Procedure Article 10.3.
I think that there will be arguments as to whether all applicants under the Hybrid Abridged Procedure must supply data, or whether they must supply data only if it is “appropriate” to do so, and if it is appropriate to supply data, exactly what data is appropriate. There will be special difficulties where bioequivalence can not be demonstrated.
• Reference Product
Current periods of data protection and market exclusivity are not harmonised. Where an abridged application is made in one Member State, and relies on a data belonging to another, what period applies? Is it the period of protection in the State for which the application is made, or the Reference State? There is no Europe wide agreement. The MHRA believes that the period of protection applied by the Authorising State is relevant, not that of the Reference State. This seems sensible to me: any contrary interpretation would undermine the ability of the Member State to choose the period of protection. But it is not clear.
• Bolar Provision
Exactly what is permitted? Are subjective intentions to be taken into account? Does the provision apply solely to ‘generic ‘ products, or also to those covered by Article 10(3), which replaces the proviso?
• Additional one year period of protection
What constitutes “a significant clinical benefit?”
I may write more when there are further developments! And I would love to hear from you if you have matters to discuss.
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