In the recent case of Accord Healthcare Ltd and another v Astellas Pharma GmbH and another  EWHC 3676 (Ch), the High Court has declared that a marketing authorisation, granted in 2005 under transitional provisions applicable following German reunification, was fully compliant with European law and the drug could therefore be relied upon as a "reference medicinal product" in accordance with Directive 2001/83/EC.
Directive 2001/83/EC (the "Directive") sets out detailed requirements that must be met by an applicant seeking marketing authorisation for a medicinal product. By way of derogation from these requirements, Article 10(1) provides that following expiry of a certain period of time (the "exclusivity period"), a generic manufacturer is entitled to obtain its own marketing authorisation without providing the results of pre-clinical tests and clinical trials if its application is for a generic of a medicinal product which has been authorised by a Member State in accordance with the Directive (a "reference medicinal product").
In July 2005, Astellas obtained marketing authorisation from the German regulatory authority ("BfArM") for its bendamustine anti-cancer product Ribomustin®. In 2013 and following expiry of the exclusivity periods in the 6-year countries, Accord applied for, and was granted, marketing authorisations in a number of European countries for its generic bendamustine product. Accord cited Ribomustin® as the reference medicinal product. However, Astellas repeatedly challenged these marketing authorisations, alleging that the approval of Ribomustin® in 2005 did not constitute a marketing authorisation within the meaning of the Directive, and therefore could not be relied upon by Accord (or any other generic manufacturer) as a reference medicinal product. In particular, Astellas argued that the 2005 marketing authorisation granted by BfArM had not been properly reviewed and/or had otherwise been revoked retrospectively. Astellas had obtained a later marketing authorisation in 2010 for its bendamustine product Levact and claimed that this was the proper reference medicinal product for the purpose of calculating the start of the exclusivity period.
Astellas's numerous challenges in the 6-year countries disrupted the launch of generic bendamustine and in some cases resulted in the automatic suspension of the marketing authorisation.
Faced with uncertainty in the 10-year countries, Accord took the unusual and proactive step of seeking a positive declaration from the High Court that Ribomustin® was the correct reference medicinal product within the meaning of the Directive, in order to clear the way for the launch of its bendamustine product in the UK. The declaration was sought before expiry of the exclusivity period.
Was the 2005 BfArM authorisation a marketing authorisation in accordance with the Directive?
The 2005 marketing authorisation granted by BfArM for Ribomustin® was an extension of a deemed authorisation that took effect by operation of law for medicinal products already in clinical use at the time of German reunification. Following submission of the required dossier, the extension was granted under s.105 of the German Medicinal Products Act ("AMG") in respect of two of the three indications sought by Astellas, but was subject to a number of conditions relating to the pharmaceutical quality of the product. In the current case, Astellas submitted that BfArM were not permitted to issue a conditional authorisation pursuant to s.105 AMG and that the marketing authorisation granted by BfArM in 2005, Astellas alleged, was therefore not compliant with the Directive. As a consequence Ribomustin® could not constitute a reference medicinal product triggering the start of the exclusivity period.
Even if the court were to consider that marketing authorisations with conditions were generally permitted under the Directive, Astellas submitted that since the conditions imposed in this particular case related to allegedly "serious deficiencies" in the dossier submitted, the 2005 authorisation was not in substance a Directive-compliant authorisation. As a consequence, Astellas argued that Ribomustin® could not be relied upon as a reference medicinal product under Article 10(1) of the Directive.
Did a settlement agreement concluded between Astellas and BfArM in 2011 render the 2005 decision void ab initio?
Following BfArM's decision in 2005, Astellas launched an appeal against BfArM's refusal to grant marketing authorisation for one of the indications sought for Ribomustin®. This appeal was eventually settled in 2011.
Astellas argued that the settlement agreement between BfArM and Astellas had retrospective effect, thereby rendering the 2005 marketing authorisation decision void ab initio for all three indications. As a consequence, the 2005 marketing authorisation for Ribomustin® did not trigger the start of the 10-year data exclusivity period provided for under the Directive and could not be relied upon by Accord (or any other generic manufacturer) for the purpose of launching a generic bendamustine product.
The Court dismissed Astellas's arguments and found in favour of Accord in all respects, granting the positive declaration sought by Accord that Ribomustin® is a reference medicinal product within the meaning of the Directive.
Morgan J. held that there were repeated references in the Directive suggesting that the competent authority, when granting a marketing authorisation, could impose conditions or post-authorisation controls. The marketing authorisation granted by BfArM in 2005 was consistent with this and the wording of the authorisation quite clearly stated that it could be suspended or revoked if the conditions imposed were not fulfilled within the required timeframe. Morgan J. also held that the conditions did not indicate there were any "serious deficiencies" or that BfArM went beyond the powers of a competent authority under the Directive in imposing them.
In relation to the settlement agreement, Morgan J. held that even if Astellas had intended to void the 2005 marketing authorisation ab initio, the legal effect of the settlement was in fact to renounce the 2005 marketing authorisation from the date of the settlement agreement i.e. from the end of 2011. In pre-settlement correspondence BfArM had repeatedly refused to annul the decision in the retrospective manner suggested by Astellas. Furthermore, under German administrative law, a lawful administrative act such as this could only be revoked prospectively, not retrospectively.
In the judgment, Morgan J. stated that the usual method for challenging a marketing authorisation was by judicial review. However, taking into account Astellas's previous pattern of challenging Accord's marketing authorisations in other countries, frequently leading to their automatic suspension, Accord sought a positive declaration from the UK Courts to obtain clarity ahead of the expected UK marketing authorisation in November 2015. Furthermore, both parties were in agreement that the declaratory proceedings would serve a useful purpose in resolving the key issues in dispute.
This case is an example of the UK Courts acting in an innovative way to resolve a large-scale commercial dispute very quickly. The trial was heard on an expedited basis, with the time from starting the action to judgment being just over four months. The case involved the consideration of complex issues of European pharmaceutical regulatory law and German administrative law and also triggered three unsuccessful interim relief applications and judicial reviews being sought against the MHRA and at least six other parties. The cases continue in various countries around Europe.
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