Masterstudiengang "Drug Regulatory Affairs"
Describe the CADREAC-procedure for a product which was authorized via mutual recognition procedure in the EU and ... ***
Andrea Hörner (Abschlußjahr: 2005)
Originally, the members of CADREAC were Bulgaria, Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia, Slovenia and Turkey. Nine of these countries joined the EU on 1st May 2004, therefore in April 2005 there were only three CADREAC countries left Bulgaria, Romania and Turkey.
The mission of CADREAC is facilitation of smooth transition of regulatory conditions in EU associated countries to achieve regulatory standards required by Acquis Communautaire (compliance to article (Art.) 6 of Directive 2001/83/EEC (cf. 7.1) amended by Directive 2004/27 (cf. 7.2): No medicinal product (MP) may be placed on the market of a Member State (MS) unless a marketing authorization (MA) has been issued by the competent authorities (CAs) of that MS in accordance with this Directive or an authorization has been granted in accordance with Regulation (EEC) No 2309/93. The authorization referred to in paragraph 1 shall also be required for radionuclide generators, radionuclide kits, radionuclide precursor radiopharmaceuticals and industrially prepared radiopharmaceuticals.), which are:
Implementation of EU regulatory standards
Involvement in professional activities within EU
Introduction of mutually recognition procedures (MRP)
Introduction of centralized procedures (CP)
Development of common strategies
Preparation of meetings
A CADREAC Standard Operating Procedure (SOP), CADREAC SOP-3 (2001) was adopted in April 2001, defining the responsibilities and function of a CADREAC secretariat (cf. 7.3). The secretariat of CADREAC is located in Romania since March 2004.
In addition to the CADREAC MSs, the following countries have the status of observers: Belarus, Bosnia-Herzegovina, Croatia, Republic of Moldova, Switzerland and Serbia and Montenegro.
The CADREAC countries developed certain guidelines and procedures as a preparation for their EU-accession, e.g. the so-called simplified CADREAC procedures:
Common procedure on the granting of MAs by CADREAC DRAs for MPs authorized in the EU by CP - in force since January 1999
Common procedure on the granting of MAs by CADREAC DRAs for MPs authorized in the EU by MRP - in force since May 2001 (The 1st revision of the guideline - published on 10th June 2001 - includes the retrospective inclusion of MPs for human use authorized in EU via MRP in the Common CADREAC Simplified System)
Common CADREAC Procedure (CCP) for retrospective inclusion of centrally authorized MPs for human use in the Common CADREAC Simplified System - in force since May 2001
The first two different CADREAC procedures - the CADREAC procedure for products authorized in EU via CP and the CADREAC procedure for products authorized in EU via MRP - offer a good possibility to register a MP, which was authorized in EU via MRP or CP, in the CADREAC countries with the respective simplified procedure. The basis for the assessment for the CADREAC DRAs is the original dossier, which was submitted and approved in EU for MRP by EU MSs (Reference Member State (RMS) and Concerned Member States (CMSs)) or for CP by European Commission (EC).
The national procedure (NP) within this thesis described in detail for Romania is a complete independent procedure, where a country specific dossier is submitted. The complete evaluation of the dossier is also done independently by the national authority (National Medicines Agency (NMA) in Romania). Both procedures CADREAC procedure for products authorized in EU via MRP and NP bear different advantages and disadvantages, as for example the following:
The CADREAC procedures offer the possibility of harmonization of labeling texts (Summary of product characteristics (SmPC) and patient information leaflet (PIL)) and the documentation of MP authorized in the EU MSs via MRP or CP with the CADREAC MSs due to the fact that the documentation and labeling documents which have to be submitted are identical to those approved in EU. In this case one identical dossier and identical labeling documents are approved in EU MSs and CADREAC countries. This is an advantage, because also life-cycle management (e.g. handling of any changes and Variations (VARs)) can be handled very simple because of identity of dossiers and labeling documents with EU.
On the other hand, this harmonization of labeling documents (SmPC and PIL) is a prerequisite for generics, but is done by the originators. Thus, generics can apply for, can get easier MAs, and can come earlier and easier to the market which is a clear advantage for generics and a big disadvantage for originators. If the product is authorized via NP in each CADREAC country the labeling documents (SmPC and PIL) are normally not harmonized. In this case, the way for generics to get MAs is more complicated due to the fact that the requirement for generics - the harmonization of SmPC and PILs - has to be done by their own and is not done by the originators. Therefore the CADREAC procedure has a clear advantage for generic companies.
Another advantage of the simplified CADREAC procedures is the benefit of time because these procedures take less time than the NP for getting the respective MA. The CADREAC procedure for products authorized in EU via MRP takes between 4 and 12 months depending on the review time in each country (shortest country is Bulgaria with 120 days, Romania needs 6 months (usually there is a delay of 3 to 4 months) and the longest country was Hungary with 12 months). The CADREAC procedure for products authorized in EU via CP takes between 2 and 7 months depending on the review time in each country (shortest country was Estonia with 2 months, Romania needs 3 months and the longest country is Turkey with 7 months).
To sum up, aspects like flexibility of the applicant/marketing authorization holder (MAH), duration of the MA procedure, evaluation procedure of the dossier, date for submission of marketing authorization application (MAA), lifecycle of a product, harmonization of dossier and labeling documents (SmPC and PIL) and costs of the procedure should be considered for the decision which procedure to be used for the MAA of a certain product in the CADREAC countries.
The future of the CADREAC procedure is influenced by the EU-review and further states to join the agreement. Due to the new European procedures MRP and decentralized procedure (DP) the CADREAC guideline for a product authorized in EU via MRP will have to be revised. Just recently, Croatia joined the CADREAC agreement.
Pages: 66, Annex 9