Marketing authorization application , EMEA

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 ... 

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). 

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. 

EMEA Guideline on similar biological medicinal products Information requirements for the marketing authorization applications 5... 

A CPMP member acts as rapporteur or corapporteur for centralized procedures and the CPMP gives an official opinion on whether an application for marketing is approvable or not. The EMEA is intimately involved in the management of this procedure up to the issue of the marketing authorization. The EMEA s involvement also includes preparation of the CPMP opinion in all 11 official EU languages. Quality management standards have been implemented for the preparation of scientific advice and opinions, and a... 

If the herbal medicinal product contains a preparation, rather than merely the herbal substance itself, the comprehensive specification for the herbal substance must be followed by a description and validation of the manufacturing process for the herbal preparation. The information may be supplied either as part of the marketing authorization application or by using the European Active Substance Master File procedure. If the latter route is chosen, the documentation should be submitted in accordance with the Guideline on active substance master file procedure" (EMEA/CPMP/QWP/227/02 and EMEA/CVMP/134/02). 

Under the centralized route, marketing authorization applications (dossiers) are submitted directly to the EMEA. Before evaluation begins, the EMEA staff first validate the application, by scanning through it to ensure that all necessary information is present and presented in the correct format. This procedure usually takes one to two working weeks to complete. Biotech-based dossiers are termed part A applications , whereas new chemical entities are termed part B applications . 

Regulatory evaluation of marketing authorization applications must be completed within strict time limits. The EM EA is given a 210-day window to evaluate an application and provide a scientific opinion. However, during the application process, if the EMEA officials seek further information/clarification on any aspect of the application, this 210-day clock stops until the sponsoring company provides satisfactory answers. The average duration of active EMEA evaluation of biotech-based product applications is in the region of 175 days, well within this 210-day time frame. The duration of clock stops can vary widely - from 0 days to well over 300 days. Most applications, however, incur clock stops of the order of 30 to 80 days. Upon receipt of the... 

It is worthwhile to note that, in the US, where the applicant will just be dealing with a single authority, there is no need to re-submit data that was previously submitted as part of an IN D application to conduct clinical trials. Instead, the applicant can cross-reference the IND file. This does not apply in Europe, because clinical trial applications will have been submitted to individual Competent Authorities, whereas marketing authorisation applications are usually submitted either centrally to the European Medicines Agency (EMEA) or collectively to a number of Competent Authorities. Thus, the files need to be self-supporting. 

The mutual recognition procedure is an alternative means by which a marketing authorization may be sought. It is open to all drug types except products of biotechnology. Briefly, if this procedure is adopted by a sponsor, then the sponsor applies for a marketing licence not to the EMEA, but to a specific national regulatory authority (chosen by the sponsor). The national authority then has 210 days to assess the application. 

A further 30 days is set aside in which any difficulties that arise may be resolved. The total application duration is 300 days. If one or more states refuse to grant the marketing authorization (i.e. mutual recognition breaks down), then the difficulties are referred back to the EMEA. The CPMP will then make a decision ( opinion ), which is sent to the European Commission. The Commission, taking into account the CPMP opinion, will make a final decision that is a binding. 

An application is submitted to the European Medicines Agency (EMEA). The EMEA evaluates the application and forwards its opinion (positive or negative for granting of a marketing authorization) to the European Commis-... 

Identical applications are submitted to those member states where marketing authorizations are sought. The first member state that reviews the application is called the Reference Member State. It notifies other states, called Concerned Member States. Concerned Member States may suspend their own evaluations to await assessment by the Reference Member State. The decision of the Reference Member State is forwarded to the Concerned Member States. If the Concerned Member States reject mutual recognition, the matter is referred to the CHMP of the EMEA for arbitration. The EMEA forwards its opinion to the European Commission, which makes the final deci-... 

The position of the regulatory authorities is best illustrated by a recent Marketing Authorisation Application by Eli Lilly (www.emea.europa.eu/ humandocs/PDFs/EPAR/cymbalta/19256704en6.pdf) for their anti-depressant duloxetine. The phase III protocols specified a repeated measures ANOVA as the primary method of analysis and the regulatory submission was based on such analyses. The CPMP, however, asked for an additional simpler analysis based on change from baseline as the outcome measure and using LOCF. 

Excipients, including those added during the manufacture of the herbal preparations, should be described according to the Note for guidance on excipients in the dossier for application for marketing authorization of a medicinal product" (Eudralex 3AQ 9A) or the Note for guidance on excipients in the dossier for application for marketing authorisation of veterinary medicinal products" (EMEA/CVMP/004/98), as appropriate. Eor novel excipients, the dossier requirements for active substances apply (refer to Directive 2001/83/EC as amended for human medicinal products and Directive 2001/82/EC as amended for veterinary medicinal products). 

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