With the intention of consolidating expertise across the European Union (EU), to improve public health, the European system of authorisation was established.
By Dr. Silke Nolkemper, EXTEDO
Following the Thalidomide disaster in the late 1950s and early 1960s, the regulation of medicine has been established, as it became apparent that it is very important to safe guard all medicines, no medicines should be marketed without prior authorization and it is important to ensure safe and effective use of medicines.
Initially, the pharmaceutical industry as Marketing Authorisation Holders (MAHs) would submit for a Marketing Authorisation (MA), mainly via the National procedure. This implied that the MA was granted for their medicinal product in one particular country only.
With the intention of consolidating expertise across the European Union (EU), to improve public health, the European system of authorisation was established. 34 regulatory agencies from the 31 European Economic Areas (28 EU Member States plus Iceland, Liechtenstein and Norway), the European Commission and EMA work together to authorise medicines. Authorisation can be via the Centralised Procedure (CP), Decentralised Procedure (DCP) or the Mutual Recognition Procedure (MRP).
Marketing Authorisation Application (MAA)
So how do companies decide which procedure to use while applying for a MA? In case of CPs, this route of authorisation is mandatory for certain types of medicines as it authorises the supply of the medicine through the EU without separate applications to individual territories. This is applicable for certain human medicines that contain a new active substance to treat conditions such as human immunodeficiency virus (HIV), cancer, diabetes etc. The scope of centralised procedure is described on the EMA (European Medicines Agency) website3. EMA is responsible for all the assessments and once the application is approved, the medicinal product can be marketed.
However, if a medicinal product does not fall under the ‘mandatory’ list of medicines registered via the centralised procedure, it is the MAH’s decision to decide on the appropriate regulatory strategy for submission of their application.
Via DCPs, MAHs can submit an application for a medicinal product simultaneously to multiple members of the European Union, and one of the member states becomes the Reference Member State. The MAH is not required to make a submission to the EMA, like in the case of CPs.
MRPs result in multiple licenses in various member states where the applications are submitted to but they can only be submitted if the medicinal product has already been registered in the EU at least once.
If companies wish to market their product in only one country within EU, the national procedure is still available as a route of application.
As highlighted EMA’s esubmission website, “the concept of eSubmission and the use of electronic format of files were first introduced by pharmaceutical companies in coordination with the EMA and “pioneer” National Competent Authorities (NCAs), under the auspices of International Council for Harmonisation (ICH)”.4
The basic concept was to reduce the amount of paper, which the European Commision agreed to and formed the Telematics Implementation Group for electronic submission (TIGes). This group consisting of members from National Competent Authorities as well as the pharmaceutical industry work together to avoid duplication of work and implement a consolidated set of guidelines for electronic submissions.
Submissions are made to the NCAs or EMA, depending on the procedure type allowing them review, approve and issue a licence. It could be for a new application, a variation or even a renewal application. An electronic submission is essentially a submission submitted electronically. One thing common with all procedures is that the use of the electronic Application Forms (eAF) is mandatory for all procedures from 1 January 2016, and must be used for all applications, such as authorisations, variations and renewals.
It is also crucial to remember that EMA often publishes news about the changes with eSubmission5. As of 1st September 2017, it was said that, “An updated version of the eSubmission Gateway XML delivery file user interface is now available”. This is often worth reading while planning submissions.
1) Centralised Procedure
As stated on the EMA’s website6, EMA now only accepts submissions received in eCTD format. Mandatory from March 2014, all eCTD submissions must be sent using the dedicated submission channels, eSubmission Gateway or the related eSubmission Web Client. These are the electronic submission channels that allow secure submission to the EMA, over the internet. Once the sequence has been submitted via the correct channels, copies of sequences are not required separately by the NCAs.
For preparation of a centralised procedure in eCTD, EMA has to be selected as “country” to create envelope and specific sections in Module 1, procedure type will be “Centralised Procedure”. An eCTD submission to the EMA will always have only one envelope.
2) Decentralised and Mutual Recognition Procedures
In July 2017, CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures- Human), published a Best Practice Guide on handling eCTD submissions for MRPs and DCPs7. The guidance highlighted the common principals between MRPs and DCPs, however there are some differences. It is also crucial to remember that all NCAs within EU (involved in MRPs and DCPs), may have additional national requirements, which should be adhered to.
When the common repository is ready, with all MRPs and DCPs, the submissions will be managed as a single eCTD to ensure identical content. However, at present the common repository is not available for MRPs and DCPs and therefore the same sequence has to submitted separately to all member states involved in the procedures. There may be certain national submissions such as an Article 61(3) that will only be submitted to one NCA and this is allowed in eCTD.
The model shown in Figure 1 can only be successful with a tracking table, which has to be maintained and included in all submissions. Within the eCTD structure, there is a separate folder in Module 1, where the common tracking table can be included. It provides a history and an audit trail of all the submissions made in case that some submissions are only submitted to single countries, as they contain country specific changes. Therefore the tracking table is crucial for the agencies to follow the submission history.
When a new MAA is submitted via a DCP, a separate Module 1 eCTD envelope is created for each of the member states involved in the procedure with the procedure type set as, ‘decentralised’. The submissions then undergoes a two-step validation. Firstly, the technical validation is completed and in case of an invalid sequence, the corrections should be made and the same sequence number should be used for a resubmission.
Following the technical validation, is the content validation. The communication regarding concerns or questions about the content; is usually done via email and a final validation response is resubmitted to all the member states involved in the procedure as a new sequence.
Once the procedure starts, any drafts responses for the RMS should be submitted outside eCTD and only the final, common response should be submitted as a new sequence to all member states involved in the procedure.
All final approved documentation should be provided to the RMS and the CMSs as the close of the DCP, with the submission type set as, ‘consolidating’. The figure below, Figure 2 demonstrates how the eCTD sequences are handled in a DCP.
Common English product information is always included in the eCTD and submitted to all the member states before closing the procedure. However, national translations should be handled outside eCTD as working documents. Upon finalising the DCP, the envelope information should be changed to, ‘mutual-recognition’ and the subsequent submissions should be handled like a MRP submission within eCTD.
Mutual Recognition Procedure
As we know, with MRPs one member state within EU has already authorised the medicinal product. This member state becomes the RMS. Prior to initiation of the MRP, the eCTD sequences are handled as part of a National Procedure. Upon submission, the CMSs use the ‘current view’ functionality to distinguish documents from the national procedure, specific to the RMS and the evolve eCTD sequences can evolve from that point onwards, as shown in Figure 3. At the start of the MRP, the submission type is set as ‘maa’, the submission unit as ‘initial’ and the procedure type as, ‘mutual-recognition’.
The technical and content validation is the same as a DCP and so is the handling of national translations.
1) National Procedures
Nationally Authorised Products (NAPs), submitted in any format, are not available via the Common Repository and must be sent separately to each NCA8.
Any submissions like variations are expected as single sequences with any response documents as a new single sequence, while maintaining national translations outside eCTD.
As there are many topics to be considered for submitting an eCTD in any of the European Procedures, the procedural guidelines from EMA and CMD(h) should be studied carefully, before preparing the eCTD submissions.