Mutual recognition between the EU member states: official framework for collaboration saves resources? Alar Irs, Estonia Pre-ICDRA meeting, Nov 28-29, 2010 Effective collaboration: the future for medicines regulation
EU? 27 countries 23 languages 497 198 740 citizens 4,324,782 sq km GDP: $14.712 trillion GDP per capita: $28,213.00
EU? Austria Belgium Bulgaria Cyprus The Czech Republic Denmark Estonia Finland France Germany Greece Hungary Ireland Italy Latvia Lithuania Luxembourg Malta The Netherlands Poland Portugal Romania Slovakia Slovenia Spain Sweden The United Kingdom GDP per capita EUR PPP 10 000 64 000
Some history re drug regulation First EU directive 1965, amended in 1975 Several agencies founded/re-shaped around that time Multi-state procedure ( 75) same dossier, 1 initial assessment, CPMP discussions, different outcomes possible, incl indications Concertation procedure ( 87) out of necessity when biologicals appeared in greater number, common decision-making Single market concept, 1985-1992 European scientific agency, 1993-1995 From 6 to 27 member states
40+ national human and veterinary drug regulatory agencies
40+ national human and veterinary drug regulatory agencies
Estonia? 45 226 km² 1.3 mill people GDP per capita 1993 $PPP 6 000 2009 $PPP 20 000 National drug regulatory authority 1991, 80 staff Joined the EU in 2004 (together with 9 others)
Political thinking pre EU accession From now on everything would be decided at the EU level
Political thinking pre EU accession From now on everything would be decided at the EU level The national regulatory function would shrink i.e. resources would be saved
Political thinking pre EU accession From now on everything would be decided at the EU level The national regulatory function would shrink i.e. resources would be saved co-operation
Political thinking pre EU accession From now on everything would be decided at the EU level The national regulatory function would shrink i.e. resources would be saved co-operation Some operate, others just co-
Political thinking pre EU accession From now on everything would be decided at the EU level The national regulatory function would shrink i.e. resources would be saved co-operation Some operate, others just co-
Authorisation output of a small EU country 400-500 marketing authorisations annually 10-20% full national assessment, to be possibly recognised by other EU countries 80-90% some form of mutual recognition 1-3 new product (AB, CV) assessments + a few generics for the EU centralised procedure
Official framework for collaboration
Official framework for collaboration Marriage is a wonderful institution
Official framework for collaboration Marriage is a wonderful institution, but who wants to live in an institution? Groucho Marx, quoted in Time, Nov 29, 2010
Official framework for collaboration May save resources or, equally, might not
Co-operation in marketing authorisation in the Coal and Steel Community was started, based on common technical requirements agreed (legislated) procedure no explicit lack of resource argument pushed by industrial policy
EU today: 2 competing MA mechanisms Centralised MA procedure (EMA co-ordinated) Handled by the EMA scientific committee (CHMP) and its rapporteurs CHMP opinion is a basis for the European Commission to issue a EU-wide MA Decentral MA procedures Mutual recognition Decentralised procedure Handled by the national agencies, coordinated by the CMDh Basis for close-toidentical national MA-s
Dictionary CHMP European Medicines Agency s Committee for Medicinal Products for Human Use The members and alternates of the Committee for Medicinal Products for Human Use (CHMP) are nominated by the Member States, in consultation with the Agency's Management Board Chosen on the strength of their qualifications and expertise with regard to the evaluation of medicines. CMDh - Co-ordination Group for Mutual recognition and Decentralised procedures, human Has been set up for the examination of any question relating to marketing authorisation of a medicinal product in two or more Member States in accordance with the mutual recognition procedure or the decentralised procedure CMDh is composed of one representative per Member State, including Norway, Iceland and Liechtenstein
Original MRP (pre-2005) The MA was issued in 1 member state To get a MA in another, a MRP had to be started Reference MS would have provided an (updated) assessment report Concerned member states were expected to recognise this
Problems with the original MRP Organisational and administrative difficulties, no detailed legislation to start with National differences in technical interpretation of European legislation National assessment and lack of mutual recognition: different scientific views of assessors Differences in national summaries of product characteristics (SPCs) for generic agents and brand-leaders (vertical disharmony) Worked with few MS-s, hesitations about 25+
Ways to improve More detailed legislation More scientific co-ordination group IT solutions: Communication and Tracking System (CTS) Decentralised procedure allowing scientific discussion during the assessment Best practice guides, e.g. Best practice guide for decentralised and MR procedures (CMDh, Rev7, March 2010)
EU decentral MA procedures Mutual recognition procedure (MRP) 1 member state (reference MS) has issued an authorisation Assessment of the first MS (reference MS) recognised (or not) Divergent positions resolved by CMDh If not, by the CHMP Decentralised procedure (DCP) No member state has yet issued an authorisation 1 member state (reference MS) doing/leading the assessment Consultations during the assessment Divergent positions resolved by CMDh If not, by the CHMP
Procedures in a flow-chart EU DCP
Procedures in a flow-chart Immigration Flow Chart Roadmap to Green Card
EU MRP http://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm
EU DCP http://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm
Contribution to the system: decentralised procedures completed 01.01.-31.12.2009
Challenge To give up re-assessment in one s own agency: How can I trust them? How can I accept them taking my decision? And I do not like that guy anyway This is a risk to public health!
This is a risk to public health!
This is a risk to public health!
risk to public health a situation where there is a significant probability that a serious hazard resulting from a human medicinal product in the context of its proposed use will affect public health.
But Any objection on the ground of a potential serious risk to public health cannot be justified by differences in national administrative or national scientific requirements, or internal national policies, unless the conditions or Article 29(1) of Directive 2001/83/EC are fulfilled.
and When issues have been previously discussed and agreed upon by Member States (MSs) either during DCPs or during MRPs, they should not be reopened for discussion during other DCPs or MRPs including the same MSs, unless new information has become available.
What can be called a risk to public health and what can not Can: there was a concern with regard to the demonstration of bioequivalence, the 90% confidence intervals for Cmin in the steady state study were outside the 80-125% limits. or: the formulation of X was considered not to be equivalent to Y as a different excipient had been used. In vitro data and supporting non-clinical PK studies were not considered sufficiently reassuring for comparable release characteristics of X and Y to waive a bioequivalence study in vivo in man. Cannot the absence of an active comparator study versus a specific medicinal product the length of the treatment varies according to national medical practices the targeted population is too narrow, and should include patients who are allergic or intolerant to medicinal products approved for the same indications a requirement to use alternative analytical methods if the methods proposed in the documentation have demonstrated their suitability
Issues need to be solved Emerging potential serious public health issues should be communicated to the RMS and applicant as soon as possible. CMSs should send their position ultimately by Day 50 in MRP, and Day 100 and Day 145 in DCP, delays should be an exception. The CMSs should clearly indicate whether their comment should be regarded as a point for consideration or as a potential serious risk to public health.
If no agreement can be reached referred to CMDh or, further, CHMP
Official framework for collaboration saves resources? Eventually, yes But needs Common technical standards and clear procedural agreement/legislation Tracking tools to support the procedure Commitment not to block the system Trust (good practice, good science, no political interference in technical decisions etc) Did not work well in the EU until there were escape routes for MS-s to avoid following the reference MS
Official framework for collaboration saves resources? Eventually, yes But needs Common technical standards and clear procedural agreement/legislation Tracking tools to support the procedure Commitment not to block the system Trust (good practice, good science, no political interference in technical decisions etc) Did not work well in the EU until there were escape routes for MS-s to avoid following the reference MS Murphy's Law of Thermodynamics: Things get worse under pressure. WAS NOT APPLICABLE HERE
Official framework for collaboration saves resources? Current EU system does not allow for diversity does not encourage matters not risk to public health market forces are countered by the national interests (keeping an agency alive) does not recognise the possibility that risk-benefit may vary between the MS-s (but it does) and that drug information (SPC, labelling) may need to be adjusted nationally has not yet identified efficiency as a goal in many aspects of drug regulation, MRP/DCP may well be an exemption
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