What requirements must be met to obtain marketing authorisation (MA) for a medicinal product? Jim Kinnier Wilson (JKW), head of the life sciences group, and Katie Gordon (KG), knowledge lawyer for the IP, IT and commercial team at Penningtons Manches LLP, consider the impact of the judgment in Accord Healthcare v Astellas.

WHAT IS THE BACKGROUND TO THIS CASE AND WHAT DECLARATIONS DID THE PARTIES ASK FOR?

JKW: The case broadly concerns the date when a medicinal product (the reference product) was authorised to be put onto the market, and thus the date when a generic copy of the reference product could be authorised. It involves complex questions of European law, of German national medicines law and of the administrative procedures of the German competent authority for medicines. More broadly, the wider dispute between the parties relates to multiple generic product marketing authorisations (and Astellas’s challenges to those MAs) in different European countries. The defendant, Astellas Pharma GmbH (Astellas) had, for a number of years marketed a chemotherapy drug under the name Ribomustin® and, more recently, under the name Levact®. This is an anti-tumour drug, whose active ingredient is known as ‘bendamustine’.

The claimant, Accord Healthcare Limited (Accord), sought and successfully obtained marketing authorisations for their generic version of bendamustine in a number of European countries (including the UK where the marketing authorisation was granted by the MHRA just before the trial started). Astellas had consistently challenged Accord’s marketing authorisations for bendamustine and during the course of the trial Astellas commenced judicial review proceedings to have Accord’s marketing authorisation quashed.

KG: The case concerned the interpretation of the community code relating to medicinal products for human use contained in Directive 2001/83/EC, as amended (the Directive). The Directive lays down the requirements which must be met by an applicant for a marketing authorisation for a medicinal product. The Directive normally requires an applicant to submit to the competent authority the results of pre-clinical tests and clinical trials so that an assessment of the safety and efficacy of the drug can be made. There is, however, a derogation from this requirement to allow an application for marketing authorisation to be made for a generic of a reference medicinal product without the applicant submitting the results of its own pre-clinical tests and clinical trials once a set period, typically referred to as the data exclusivity period, has elapsed. The data exclusivity period relevant is usually 10 years between the issue of the marketing authorisation for the reference medicinal product and the first marketing of the generic product. 

Accord argued that an authorisation for Ribomustin obtained by Astellas in Germany in July 2005 counted as an initial marketing authorisation for the purposes of the Directive and for the 10 year data exclusivity period. Astellas argued that the 2005 authorisation did not amount to a marketing authorisation in accordance with the Directive and that the first marketing authorisation which is relevant for present purposes was in fact one granted by the French competent authority, for Levact, in July 2010; thus, they say, the data exclusivity period runs from that later date.

JKW: The history of bendamustine’s market presence was complicated by that fact that, originally, it had been developed and first marketed in East Germany prior to re-unification. When Germany was re-unified in 1990, temporary transitional arrangements were put in place to allow medicines which had been on the market in East Germany to remain on the market throughout Germany. Holders of such deemed authorisations needed to apply for re-registration under what was known as the Nachzulassung procedure, the objective of which was to produce a marketing authorisation that would comply with the Directive. The 2005 marketing authorisation was obtained by Astellas under the Nachzalussung procedure for only two of the four therapeutic indications sought by Astellas: non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). The authorisation was refused for chronic lumphatic leukaemia (CLL) and breast cancer. As had been the practice under that procedure, the authorisation was made subject to conditions to be complied with post grant. The evidence showed that these appear to have been complied with.

Astellas appealed the refusal only of the CLL indication, acknowledging the authorisation for NHL and MM as modified and restricted. That appeal was subsequently suspended, with the proceedings being stayed, until it was eventually withdrawn in 2011, once Astellas and the German authority had reached an agreement on how to approach the 2005 authorisation. Effectively the parties were to treat the 2005 authorisation as a fictitious authorisation which would be waived by Astellas (Mr Justice Morgan subsequently found that, as a matter of German law, such a waiver could not be retrospective from the date it had been agreed, so the effect of the waiver only ran from 31 December 2011 (by which time Astellas had received the French marketing authorisation for Levact), see later.)

In this case, Astellas argued that its 2005 marketing authorisation was not granted in accordance with the Directive since the dossier of pre-clinical tests and clinical trials it had submitted pursuant to the application was incomplete. In addition it argued that it was not possible under the Directive for the German authority to impose post-grant conditions of the type included on the 2005 marketing authorisation. Astellas further argued that its appeal against part of its 2005 marketing authorisation had resulted in the annulment of that marketing authorisation. 

Accord took the somewhat unusual step of seeking a declaration from the Chancery Division of the English High Court that they were entitled to a UK marketing authorisation for their generic version of bendamustine. Astellas counterclaimed for a declaration that Accord was not so entitled. 

WHAT WAS THE OUTCOME?

KG: The High Court found that the German authority was entitled to impose the post grant conditions in the 2005 MA. It also found that Astellas was incorrect in its assumption that its settlement of the appeal resulted in the annulment of the 2005 marketing authorisation. At the time of the settlement of the appeal Astellas had the benefit of a marketing authorisation for use in treating NHL and MM and a deemed authorisation in respect of treating CLL (under the transitional regime). The settlement resulted in Astellas renouncing the deemed authorisation for CLL but there was a question as to the effect of the settlement on the marketing authorisation for NHL and MM. Mr Justice Morgan held that it was not open to Astellas and the German authority to agree that the July 2005 decision was non-definitive retrospectively. In his view Astellas and the German authority plainly intended that the July 2005 marketing authorisation for NHL and MM would not continue in effect after 31 December 2011. He considered the effect of the settlement to be that Astellas renounced both the July 2005 marketing authorisation and the deemed authorisation for CLL with effect from 31 December 2011.

The declaration was granted in favour of Accord. The 2005 marketing authorisation complied with the Directive and had been granted in accordance with Article 8 of the Directive. Astellas’s 10 year exclusivity period commenced in 2005 not 2010. Consequently Accord was able to launch its generic version of bendamustine.

WAS IT RIGHT TO HAVE CHANCERY PROCEEDINGS HERE, AS WELL AS THE JUDICIAL REVIEW PROCEEDINGS?

JKW: The judge was clearly very unhappy about the procedure adopted in this matter. As the real concern was whether or not the MHRA could legitimately grant and authorisation for generic bendamustine, judicial review of that decision ought to have been the procedure followed.

Indeed Mr Justice Morgan voices his concern as to the approach the parties adopted. Particularly that neither party sought to join the MHRA as a party to the proceedings despite the fact that around the same time as bringing the Chancery proceedings Accord applied to the MHRA for a marketing authorisation in the UK for its generic version bendamustine. Just before the trial began the MHRA granted Accord its marketing authorisation. Once this grant had been made judicial review of that decision would seem the most appropriate way for Astellas to challenge the decision. During the course of the trial, Astellas issued proceedings for judicial review seeking an order quashing the decision of the MHRA.

Judicial review is very different from the procedure followed in Chancery proceedings. In particular, a judicial review claim may only be brought with the permission of the court, which must be satisfied that the claim gives rise to an arguable case for judicial review. In contrast in Chancery the parties were able to bring their claim and counterclaim without obtain the court’s permission and so had side-stepped the requirement of permission for a judicial review. Also in Chancery proceedings, the parties proceed on the basis that the issues between them will be the subject of oral evidence and cross-examination.

In light of the above, Mr Justice Morgan adjourned the trial on its first day so the parties could consider with the MHRA:

  • how the matter might be progressed; and
  • whether the time set aside for the trial could be used for proceedings in which the MHRA could participate.  

In the event it became clear that it was not realistic to expect the MHRA to participate in any hearing to determine the issues raised by the parties, or if different, the issues which might arise in appropriate judicial review proceedings.

KG: Clearly the judge would have preferred that the Chancery proceedings had not been brought and did not continue, as his strong reaction at the beginning of the trial was that the Chancery case should not go ahead. However, as the parties to the proceedings were united in stressing the importance to them of the proceedings continuing and in the absence of anyone, such as the MHRA, suggesting otherwise, Mr Justice Morgan considered that it would be going too far if he, of his own initiative, refused to try the action.

He did emphasise that the procedure adopted had not been approved by the court as one which should be followed in other cases.

A CJEU REFERENCE WAS FOUND PREMATURE, BUT IS ONE NEEDED AT SOME STAGE ON THE ISSUES RAISED HERE?

JKW: Astellas applied for a CJEU referral both before and after the trial, but before judgment. Whether a reference is eventually needed may depend on either Astellas’s application for judicial review of MHRA’s decision to grant marketing authorisation to Accord or any appeal, as Astellas has indicated that it intends to appeal the judgment to the English Court of Appeal. Whether a CJEU reference is needed will depend on such appeal and whether the issues of EU law to be referred are likely to be determinative of the dispute. 

DOES THIS DECISION HAVE ANY BROADER EFFECT ON THE INDUSTRY OR THE LAWYERS WORKING WITHIN IT?

KG: This is a long, complex judgment, but clearly written. So, whilst the case provides useful clarification on the interpretation of the Directive in relation to conditional marketing authorisation, the circumstances of the case are quite unusual in that it relates to a medicine developed in East Germany pre-unification and the process applicable to the conversion of the marketing authorisation for that medicine to an EU compliant marketing authorisation. In that respect it is likely to be limited in its application.

It is also important to note that, procedurally, the judge stressed parties in other cases would not do well to follow this case, which is not a procedure which has been approved by the court. It would seem that the best course would be judicial review of the MHRA’s decision to grant, once that had been made. 

This article was published in Lexis®PSL in January 2016.