Clinical trials for generics, biosimilars and, in some European countries, even innovative products
In order to market a medicinal product, a manufacturer must first obtain regulatory approval by conducting clinical tests and trials to prove that the product is safe and effective. However, when the medicinal product is a generic(1) or biosimilar(2) product, a company can avoid having to carry out full trials by relying on at least some of the data submitted by the original applicant for marketing authorisation in connection with the original (reference) medicinal product. To use this so-called abridged procedure for obtaining marketing authorisation, however, it is necessary to demonstrate that the generic/biosimilar version is bioequivalent to the approved reference medicine.
If the medicinal reference product is patent protected, then there is a real risk that acts relating to that product infringe the patent. Historically, this risk of patent infringement potentially deterred generics manufacturers from carrying out the tests required to obtain marketing authorisation until after patent expiry, resulting in a delay of market entry of generics.
Many EU member states have an “experimental use exemption” which exempts certain experimental activities from patent infringement, but the scope of these provisions varies widely among the member states. Thus, whilst in some countries, notably Germany, the experimental use exemption was interpreted by the courts to exempt all experimental uses aimed at gaining knowledge, in others, such as the UK, the exemption was interpreted much more narrowly.
In an attempt to harmonise the position in Europe and to speed up the entry of generic products onto the market after patent expiry, the so called “bolar exemption” was introduced by the European Union (EU) to exempt from patent infringement the tests and trials necessary to use the abridged procedure for obtaining marketing authorisation.
The bolar exemption is governed by European Directive 2001/83/EC on the Community Code relating to medicinal products for human use, as amended by European Directive 2004/27/EC, particularly Article 10 thereof.
Article 10(6) excludes from infringement of patent rights or supplementary protection certificates (SPCs): “Conducting the necessary studies and trials with a view to the application of paragraphs 1, 2, 3 and 4.”. Paragraphs 1-4, i.e. Articles 10(1)-(4) of the Directive, concern the provision of data during the marketing approval process.
Although the Directive was aimed at harmonising the position in the EU member states, the implementation of the Directive into national law has not been uniform, resulting in significant differences between the member states.
Thus, whilst some countries, notably the UK, have adopted an exemption that is limited to generic or biosimilar medicinal products, others, including Germany and France, have adopted an exemption that is not so limited, extending also to innovative medicinal products.
It should be noted that in February 2013, in response to a consultation issued by the UK Intellectual Property Office on clinical trials and patent infringement, the UK Government indicated that a change in legislation should take place to exempt from infringement the activities required to secure regulatory approval to market innovative drugs, and also activities necessary for health technology assessment e.g. data to support assessment by the National Institute for Health and Clinical Excellence (NICE). An amendment to the UK Patents Act 1977 is expected in 2014.
The Directive does not provide any guidance as to which acts are exempt from infringement, referring merely to “conducting the necessary studies and trials”. It is widely accepted that actual trials testing the safety or efficacy of the medicinal products would fall within the scope of this exemption, but there has been uncertainty regarding other acts, such as the manufacture, supply or import of the medicinal product.
In the UK, the Intellectual Property Office has issued a helpful but non-binding guidance note setting out which acts it believes are covered by the UK bolar exemption, including manufacture and import. Other national patent offices have been less forthcoming.
A particularly contentious issue is whether a third party is free to supply the medicinal product to the party carrying out the trials necessary to obtain marketing authorisation. A referral to the Court of Justice of the EU has recently been made in this regard by a German court. An English translation of the referring decision may be found here.
Data exclusivity and market exclusivity
It is recognised that allowing the producer of a generic or biosimilar medicinal product to use an abridged marketing authorisation gives the producer of the generic or biosimilar an advantage. To redress the balance and reward innovators, the Directive sets a period of “data exclusivity”, during which the data submitted in connection with an innovative drug may not be used by third parties.
In addition, a further period of "market exclusivity" runs from the end of the data exclusivity period and prevents manufacturers of generic/biosimilar medicinal products from placing their products onto the market. The combined period of data exclusivity and market exclusivity is about 10 years in Europe.
Detailed further information regarding these forms of exclusivity, as well as regarding the requirements for obtaining marketing authorisation for generics and biosimilars may be found on the website of the European Medicines Agency.