Transcript THE UK EXPERIENCE RELATED TO CASE C

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?
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.
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.
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.
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.
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.
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.
October 2010: Article 31 referral
to CHMP by UK
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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.
 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.
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.
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.
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.
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.
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.
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.
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.
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.