1. THE UK EXPERIENCE RELATED TO ESCITALOPRAM seeking clarity in the EU interest IS THE UK’S REFERRAL TO CHMP UNDER ARTICLE 31 OF DIRECTIVE 2001/83 LEGITIMATE?

2. CURRENT SITUATION The UK competent authority (Medicines and Healthcare products Regulatory Agency (MHRA)) is considering whether to: suspend marketing authorisations for generic escitalopram which have been granted under Article 10.3 grant marketing authorisations for generic escitalopram which have been the basis of an application under Article 10.3 but which could potentially be granted under Article 10.1.

3. History of Escitalopram in EU Escitalopram was authorised in Dec 2001, with Sweden as RMS, under Article 8 It was regarded by Sweden as a NAS, and not challenged by anyone in their designation as a NAS. If regarded as a new active substance (NAS), it will have data protection until December 2011. Lundbeck (reference products owner) has a supplemental protection certificate on escitalopram until 2014.

4. Situation in UK The MHRA has authorised 7 generic escitaloprams under Article 10.3, cross referring to the branded citalopram to get around the protection on the escitalopram data data package we all now accept is not adequate if we exclude studies that Lundbeck conducted as part of their programme and are therefore protected. None are marketed because of the patent situation. We also have two applications on hold in the clock stop phase of DCP, both submitted under 10.3, but now asking if they can switch to 10.1.

5. July 2009: Article 30 referral to CHMP by UK UK raised a referral to CHMP on the grounds that NL had suspended escitalopram, and we had, therefore a divergent decision across the community. 1. If two or more applications submitted in accordance with Articles 8, 10, 10a, 10b, 10c and 11 have been made for marketing authorisation 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, hereinafter referred to as ‘the Committee’, for the application of the procedure laid down in Articles 32, 33 and 34.

6. Subsequent history Following legal action, subsequently NL reinstated the marketing authorisations, however changing the legal status to 10.1, and therefore stating that the reference escitalopram is not a NAS, contrary to the Swedish position. In making the referral we were prevented from asking the only really relevant question which is whether escitalopram is a NAS or not. We then asked a narrow question - if 10.3, is the data sufficient to bridge to citalopram. CHMP concluded that it was not. The Commission then declined to adopt the opinion because they claim there was no longer a divergent position - NL had no longer suspended the product.

7. The UK’s view Escitalopram should not be regarded as a NAS The Commission in 2006 has said it was designated as such, therefore that should stand, but in the same communication they opened the door to allow Art 10.3 applications cross referring to citalopram The UK also considers that once a product is authorised, the legal base cannot change from Art 10.3 to 10.1, so we cannot follow the NL position in amending the current authorisations.

8. October 2010: Article 31 referral to CHMP by UK Submitted to EMA on 19 October 2010. Question 1: Whether escitalopram and citalopram differ significantly in properties with regard to safety and/or efficacy such that they should not be considered to be the same active substance, according to Article 10.2(b) of Directive 2001/83/EC as amended If the Community were to say it is not a NAS, then we would accept 10.1 applications without the need to bridge at all (for existing licenses we would have to invite a new MR application). If it is a NAS we would then suspend the national licenses, and could not accept 10.1 as a legal base.

9. Question 2: If escitalopram and citalopram are not considered scientifically to be ‘the same active substance’ whether it is possible within the scope of the Directive to allow an application for escitalopram under Article 10.3 using citalopram as the reference medicinal product since the reference medicinal product in that case should be escitalopram.

10. The legal tests Article 31 The Member States or the Commission or the applicant or the marketing authorisation holder shall, in specific cases where the interests of the Community are involved, refer the matter to the Committee for application of the procedure laid down in Articles 32, 33 and 34 before any decision is reached on a request for a marketing authorisation or on the suspension or revocation of an authorisation, or on any other variation to the terms of a marketing authorisation which appears necessary, in particular to take account of the information collected in accordance with Title IX. Article 33 Within 15 days of the receipt of the opinion, the Commission shall prepare a draft of the decision to be taken in respect of the application, taking into account Community law. EU institutions can only act within the powers conferred. So the Commission can act only if the conditions of Article 31 are met.

11. The Commission’s initial response By letter of 21 October, the EMA sought the advice of the Commission as to whether the Commission considers it legitimate that the CHMP should address the question of whether escitalopram is a NAS. The Commission’s response “serious” doubts exist as to whether the UK’s Article 31 reference can be triggered reasonable doubts exist as to whether the UK authority can envisage a suspension of the concerned marketing authorisations in these circumstances.

12. Community interest Community interest is a necessary condition. Adopting a natural reading, any interest which affects more than one Member State is a Community interest. The Commission have said in their reply to the Agency that Article 31 does not specifically give the Commission the role to assess whether a question referred by a Member State is of the Community interest.

13. CHMP opinion needed in order to decide on whether marketing authorisations should be granted, suspended or revoked Following the decision of the Commission based on the Opinion of the CHMP, such a suspension would be carried out under Article 116, second paragraph (text in bold) An authorisation shall also be suspended, revoked, withdrawn or varied where the particulars supporting the application as provided for in Article 8 or Articles 10, 10a, 10b, 10c and 11 are incorrect or have not been amended in accordance with Article 23, or where the controls referred to in Article 112 have not been carried out. In other words, suspension would be on the basis of a finding by the competent authority that the data submitted in order to support the application was no longer correct to support the legal basis chosen by the applicant.

14. Power to suspend under the second paragraph of Article 116 The following are not essential for the application of this power– that the data should be relating to therapeutic efficacy or the risk-benefit balance of the product or its qualitative and quantitative composition that there must be new data arising from adverse reactions in use supplied under Title IX that there must be new data which suggests that the original dossier was incomplete.

15. The following are not relevant issues ONE The fact that a procedure governed by Article 28 is complete. Such a conclusion does not find any support in the wording of the Directive. The circumstances which have given rise to the UK referral are not typical ones for an Article 28 procedure. They are unusual and that is why recourse to Article 31 is needed. TWO The fact that the questions could have been raised in the Article 28 procedure We cannot assume that the Commission would have agreed to these questions being raised at that time. This is not relevant to the construction of Article 31.

16. The following are not relevant issues THREE The time limits in Article 29 Article 29 relevant at all since no issues of serious risk to public health arose with the procedure, or could have arisen on the basis of the questions raised in the referral. Thus the time limits in Article 29 have no relevance. FOUR The fact that an EU decision based on an Article 31 referral could result in interference in a marketing authorisation, on the principle that marketing authorisations are “rights” which cannot be challenged in the absence of new scientific data or new information. Directive 2001/83 alone sets out the circumstances when a competent authority may lawfully interfere with a marketing authorisation, and when such circumstances are present the authority may lawfully take such action without any redress being available to the marketing authorisation holder.

17. Conclusion The UK waits for a convincing explanation about these doubts. These questions must be decided at EU level and Article 31 provides the perfect mechanism for this to happen. The matter is urgent. Failure to resolve it undermines the internal market and restricts patient choice.