The centralized procedure

Unlike the FDA, the EMEA itself does not directly undertake appraisals of drug dossiers submitted to support marketing authorization applications under the centralized procedure. Instead (as discussed in detail below), they forward the dossier to selected national EU regulatory bodies, who undertake the appraisal, and the EMEA makes a recommendation to approve (or not) the application based upon the national body s report. The overall role of the EMEA is thus to coordinate and manage the new system. The EMEA s annual budget is of the order of 120 million. The key objectives of the EMEA may be summarized as  

Under the centralized procedure, applications are accepted with regard to (a) products of biotechnology (b) NCEs (drugs in which the active ingredient is new). Biotech products are grouped as list A and NCEs as list B . Marketing approval application for biotech products must be considered under the centralized procedure, whereas NCEs can be considered under centralized or decentralized mechanisms. 

Upon receipt of a marketing authorization application under centralized procedures, the EMEA staff carry out an initial appraisal to ensure that it is complete and has been compiled in accordance with the appropriate EU guidelines (Box 4.4). This appraisal must be completed within 10 days, at which time (if the application is in order), it is given a filing date. The sponsor also pays an appropriate fee. The EMEA then has 210 days to consider the application. In the case of human drugs, the application immediately comes before the CPMP (which convenes for 2-3 days each month). 

Two rappoteurs are then appointed (committee members who are responsible for getting the application assessed). The rappoteurs generally arrange to have the application assessed by their respective home national regulatory authorities. Once assessment is complete, the reports are presented via the rappoteur to the CPMP. After discussion, the CPMP issue an opinion (i.e. a recommendation that the application be accepted, or not). This opinion is then forwarded to the European Commission, who have another 90 days to consider it. They usually accept the opinion 

The dossier submitted to EU authorities, when seeking a manufacturing authorization, must be compiled according to specific EU guidelines. It generally consists of four parts as follows  

Part I (A) contains information which identifies the product, its pharmaceutical form and strength, route of administration and details of the manufacturer. The summary of product characteristics summarizes the qualitative and quantitative composition of the product, its pharmaceutical form, details of pre-clinical and clinical observations, as well as product particulars, such as a list of added excipients, storage conditions, shelf-life, etc. The expert reports contain written summaries of pharmaceutical, pre-clinical and clinical data. 

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The final option is the Centralized Procedure. This is available for a defined list of product types (included in an Annex to the relevant Regulation) and for Orphan Drugs as defined by the Orphan Drug Committee. This procedure involves the appointment of... 

The Committee for Medicinal Products for Human use (CHMP). This committee is composed of 35 technical experts drawn from the various EU member countries. It is primarily responsible for formulating the EMEA s opinion on any medicinal product being considered for marketing approval under the centralized procedure. 

Centralized Procedure Under the European Community Regulation 726/2004 and Directive 2004/27/EC, the Centralized Procedure (also known as Community Authorization Procedure) is a single authorization procedure that is mandatory for medicinal products of the following categories ... 

Decentralized Procedure This is applicable where authorization has not yet been approved in any member state. The applicant may apply for simultaneous authorization in more than one ELI member state for medicines that do not fall within the mandatory scope of the centralized procedure. 

For our purposes, the committee for drug approval is the CHMP. Applications are submitted to the EMEA according to the centralized procedure. The review process is described in Section 8.3. In 2006 the CHMP provided 78 opinions (decisions) on medicinal products, of which 5 were negative (rejected). 

The CTDs were implemented in July 2003. They are format-based documents for submission to the regulatory authorities the country-specific process of review, for example, via the IND and NDA of the United States or the Centralized Procedure of the EMEA, is not affected. The harmonized CTDs help to reduce cost and accelerate approval time. Figure 7.1 shows the CTD structure five modules with Module 1 for regional administrative information specihc to each country. Module 2 on summary of quality, nonclinical and clinical. Module 3 on quality. Module 4 on nonclinical study reports, and Module 5 on clinical study reports. 

Submission Details for Centralized Procedure This procedure was effective from 1995 with further amendments effective from November 2005. Six months before submission, the pharmaceutical company wishing to apply for marketing authorization via the Centralized Procedure notifies the EMEA of its intention and expected submission date. This notification is required to be accompanied by a number of items, for example ... 

Justification for evaluation under the Centralized Procedure (refer to Parts A and B Products designation)... 

There are two stages for the Centralized Procedure. The first phase is divided into the primary evaluation phase and secondary evaluation phase. In... 

Describe the Centralized Procedure in Europe for drug approval. Compare and contrast the Centralized Procedure with NDA/BLA. 

Refer to Section 8.3.2. Note the requirement for the Qualified Person and Expert Reports in Europe. There are no separate applications in the Centralized Procedure for small and large molecule drugs. 

In Europe, inspections are conducted by member states on behalf of the European Union. For drugs approved under the centralized procedure, inspections are coordinated by the European Medicines Agency (EMEA refer to Sections 7.3 and 8.3). For countries that are members of the Pharmaceutical Inspection Cooperation Scheme (PIC/S see Section 7.13), there is mutual recognition of inspections performed by members. 

Source EMEA Inspections. Good Manufacturing Practice An Analysis of Regulatory Inspection Findings in the Centralized Procedure, Doc. Ref. EMEA/INS7GMP/23022/2007 [accessed August 28,2007]. 

Management and follow-up of marketing authorization applications under the centralized procedure,... 

In the centralized procedure, one license to market the drug in all of the EU is issued, and in principle there is only one evaluation of the dossier. In fact, both a rapporteur and corapporteur are appointed and eaeh assesses the dossier with its own... 

Should no agreement be reached within the MRFGWMRFG, the matter is sent to the CPMP/CVMP for an opinion. Thereafter the procedure is similar to that of the centralized procedure, the end result being a commission decision after which national licenses must be issued within 30 days. 

The Agency is utilizing modern information technology techniques to assess the quality and safety of new substance drugs that companies would like to make available within the EU. Application by a sponsor is directed to the team of experts in London following the centralized procedure. Also, if necessary, the Agency can call upon a very effective network of experts situated in 30 countries. 

In summary, given the rigor of the centralized procedure and transparency of data required, the rationale is deemed to be important for maximizing the impact and political acceptability of the processes. It is, therefore, prudent to engage the services of a consultant who is well versed with the procedural method used by the Agency. By so doing, an applicant would be able to maximize the time and expense judiciously for all the pertinent parties concerned so that a new medicine may be brought to market within a reasonable period of time. 

Council Regulation 726/2004/EC (updates and expands the previous regulation 239/1993/EC), which mainly concerns the duties of the European Medicines Agency (EMEA), establishment of the Committee for Medicinal Products for Human Use (CHMP), and the scope and mechanisms of the centralized procedure for marketing authorization applications (MAAs) and pharmacovigilance issues. 

Independent National Procedure If a company wishes to market a product in one country only and there are no legal obligations to use a route other than the national one (which would apply if the type of drug or therapeutic area were within the scope of the centralized procedure), then an application can be made to one health authority, leading to a marketing authorization in that country alone. 

Centralized Procedure (CP) This is the procedure of most interest for biopharmaceuticals, as this is the mandatory route for review and approval of such drugs in the European Union. In the centralized procedure a single application is submitted to the European Medicines Agency (EMEA). A variety of presubmission activities, starting six months before the intended start date of the centralized procedure, are required [8], Two initial assessments by a Rapporteur and Co-rapporteur national authorities (one from each of two member states chosen by the EMEA) are made, leading to Day 80 Critical Assessment Reports. A consolidated list of questions (LoQ) is provided to the applicant at Day 120 when there is a clock stop, normally of three months, to allow the preparation and submission of responses. Following satisfactory negotiation of other steps in the procedure, the Committee on Human Medicinal Products will recommend authorization at Day 210, with authorization by the Commission at Day 277. 

The current CP application fee is 232,000 Euros for a single strength associated with one pharmaceutical form. Although the fees are high and the Committee on Human Medicinal Products review is extremely thorough, if successful the centralized procedure leads to an authorization that is valid in all European Economic Area countries, and for this reason is attractive to companies that have a presence in only one or a few European countries. 

The basic problem of this suggestion was that the chirality descriptors obtained by the central procedure are the opposite of those derived from the planar approach. Schlogl consequently changed his stereochemical nomenclature [5,9] and. 

There are two European procedures for obtaining a marketing authorization in more than one country belonging to the EU. These are the Centralized Procedure and the Decentralized or Mutual Recognition Procedure. 

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