Data exclusivity and definition of a new active substance: suspension of generic escitalopram-containing medicines by CHMP


An opinion of 18 February 2010 by the CHMP confirmed that marketing authorisations (MAs) for a group of generic escitalopram-containing medicines which had been authorised using the decentralised procedure (DCP), should be suspended. The rapporteur was Dr Barbara van Zwieten-Boot of the The Netherlands, and co-rapporteur was Dr Ian Hudson of the UK. 

The opinion only applies to generic escitalopram-containing medicines of the following companies: Tiefenbacher, Centrafarm, CT-Arzneimittel, Hexal, Ratiopharm Nederland, Sandoz and Winthrop Arzneimittel which were authorised via a DCP where The Netherlands was the reference Member State.  The concerned Member States were Austria, Belgium, Germany, Hungary, Lithuania, Luxembourg, Portugal, Slovenia and the United Kingdom.

The referral to the CHMP was made under Article 30 of Directive 2001/83/EC which states:

“Article 30

1. If two or more applications submitted in accordance with Articles 8, 10, 10a, 10b, 10c and 11 have been made for MA for a particular medicinal product, and if Member States have adopted divergent decisions concerning the authorisation of the medicinal product or its suspension or revocation, a Member State, the Commission or the applicant or the marketing authorisation holder may refer the matter to the Committee for Medicinal Products for Human Use,”.

This matter was referred by the UK regulatory agency, the MHRA, after the Dutch Regulatory Authority (MEB) suspended the MAs in The Netherlands, for a maximum of one year, on 29 April 2009.  The suspension of the MAs in The Netherlands followed objections filed by Lundbeck pursuant to the Dutch General Administrative Law Act.  The start date for the Article 30 referral was 24 September 2009. 

The CHMP evaluated the data in the application that was not considered to be protected under the Data Exclusivity rules, and concluded that there was insufficient evidence to show that the generic product had comparable effectiveness and safety as the reference medicine. 

Proceedings in The Netherlands

In parallel, on 15 October 2009, the Court of Haarlem heard the appeal to the decision of April 2009 to suspend the MAs, and in its judgment handed down on 11 December 2009 overturned the decision.  The court decided not to wait until the outcome of the Article 30 referral, and gave the MEB ten weeks on which to decide again on Lundbeck’s objection. 

Following this judgment, the MEB held a new hearing on 19 January 2010, confirming the decision to grant the MAs and that the legal basis for grant is article 10(1) of Directive 2001/83/EC.  Like the court, the MEB saw no reason to defer their decision until the outcome of the referral proceedings had been completed. 

The reason given by the MEB for not waiting for the outcome of the referral proceedings is that the time when the European Commission will make their decision based on the CHMP’s opinion is not known.  Also the CHMP in its referral did not explicitly assess the issue of the new active substance status and dossier protection; it refers exclusively to the suspension of the MAs granted previously by the MEB based on article 10(3) of the Directive.

New active substance

The Swedish Authority, the MPA, granted the first MA for escitalopram (under brand-name Lexapro, also marketed as Cipralex) in the European Community in December 2001. The authorisaton for Lexapro is based on Article 8(3) of Directive 2001/83/EC. 

Escitalopram is the active S(+) enantiomer.  The racemate, citalopram was first authorised in the European Community also by Sweden in 1989 (under the brand-name Cipramil). 

On 19 May 2006, the European Commission informed the CMD(h) that information from the MPA and Lundbeck confirmed that the MA for escitalopram granted to Lundbeck was granted in 2001 according to Article 8 of Directive 2001/83/EC as a new chemical entity, and this was not questioned during the subsequent mutual recognition procedure.  Therefore, the European Commission confirmed that data protection time (six/ten) years counted from 2001 for escitalopram has to be respected by generic companies and the competent authorities of the Member States.  They also stated that companies referring to the medicinal product, citalopram, “no concerns regarding violation of data protection apply”.  The MPA confirmed that Cipralex (escitalopram) is validated and approved as a new active substance.

Following the hearing of 19 January 2010, the MEB considered in their decision the definition of a new active substance, and along with the definition of a generic product.  The MEB concluded that for the application of 10(1) of Directive 2001/83/EC that it must be assumed that isomers or mixtures of isomers are considered to be “the same active substance” unless they differ significantly with regard to safety and efficacy.  In the absence of a legal definition of “differ significantly in properties with regard to safety and efficacy”, the MEB looked at what regulatory authorities do, and concluded that this was akin to placebo controlled clinical trials, where differences between the placebo and the active substance have to be both statistically and clinically significant.  The MEB concluded that the differences between escitalopram and citalopram regarding safety and efficacy are not clinically relevant.

Whether or not this interpretation is correct may be clarified when the General Court (formerly the Court of First Instance) makes its judgment in Case T-275/09 Sepracor Pharmaceuticals (Ireland) v Commission regarding eszopiclone.

Sepracor submitted an application for an MA for Lunivia (containing eszopiclone) to the EMA on 23 July 2007, and in October 2008 received a positive opinion from the CHMP that it should be granted an MA; but the CHMP also recommended that it should not be granted “new active substance” status.  This was because eszopiclone was not considered by the CHMP to be significantly different to zoplicone with regard to safety and efficacy.  Following submission of further data by the applicant, this opinion was confirmed in February 2009, and as a result Sepracor withdrew its application in May 2009, before the Commission decision to grant the MA.  Sepracor stated that this opinion compromised the commercial viability of launching the product in Europe. 

Sepracor has brought this case to annul the decision by the Commission that the "eszopiclone" contained in it was not a new active substance under Article 3(2) (a) of Regulation N° 726/2004.  In support of its claims Sepracor says that there was a failure to apply the correct legal criteria for a new active substance.