eCTD: Guide Lines

At a first reading the definition that EMA provides of eCTD is rather cryptic.

The electronic common technical document (eCTD) shall allow the electronic submission of the common technical document (CTD) by the applicant to the regulatory authority. Although the table of contents is consistent with the harmonised CTD, the eCTD also provides a harmonised technical solution for the implementation of the CTD by electronic means.In other words, an eCTD is the presentation of PDF documents, stored in the eCTD directory structure, accessible through the XML backbone and with the file integrity guaranteed by the MD5 Checksum.
Let’s try to simplify it.

What is the eCTD?

The electronic Common Technical Document is the electronic format of the Common Technical Document (CTD). The CTD is a document defined as a “dossier” that contains all the information related to the quality, safety and efficacy of a medicinal product, structured according to a standardized format that is common in all countries participating in the ICH guidelines. Both documents are organised into five modules: Module 1 contains regional administrative information and is mainly country-specific, Module 2 summarises the data contained in the dossier, Module 3 quality data, Form 4 preclinical data and Form 5 all clinical study data related to that medicinal product.

What’s the CTD for?

The CTD is the document necessary to obtain the Marketing Authorisation (AIC) of a medicinal product for human use from the competent authority. In addition to the application for registration of the drug, it also serves to manage all the requests regarding the life cycle of that product (called “Lifecycle”): variations, renewals, PSUR (Periodic Safety Update Report), Response Document, ASMF (Active Substance Master Files).

What’s the eCTD for?

The electronic Common Technical Document allows the electronic presentation of the paper document by the applicant (the pharmaceutical company) to the competent authority (the regulatory agency). In general, it facilitates the exchange of information, ensures the security of the transmitted data and facilitates both the creation phase for the applicant and the consultation by the CTD Regulatory Agency.

Who is the competent authority?

In the European Union it is the EMA (European Medicines Agency) which approves or rejects, modifies or suspends the marketing authorisation of medicinal products evaluated through a centralised procedure valid in all countries of the European Economic Area.
For mutual recognition (MRP) and decentralised (DCP) procedures, the competent national authorities of the reference state (Reference Member State, RMS) and interested party (Concerned Member State, CMS) are responsible for issuing and maintaining the AIC, supported by the Cmdh (Co-ordination group for Mutual recognition and Decentralised procedures – human), a group created to coordinate the authorisation and pharmacovigilance activities of medicinal products for human use within these procedures. In Italy, the competent national authority for the regulatory activity of medicines managed under the national procedure is a public body called AIFA.

Since when are CTD and eCTD mandatory formats?

While the first has become the mandatory format for all applications for registration submitted in the European Union and Japan and the format strongly recommended in the United States (Directive 2003/63/EC) in 2013, the second became mandatory for all other types of requests (baseline, renewals, variations, PSUR, ASMF) submitted in the European Union, only in 2018.
In Italy the electronic Common Technical Document has become mandatory for all medicines registered through the national procedure from 2019.

Let’s go back to the definition of eCTD:

The eCTD is the electronic format of the CTD. Their structure is equivalent but instead of being in paper format, the documents that compose it consist of PDF files.
The files shall be separated by chapter and submitted by the applicant to the competent authority as a whole, referred to as “sequence”.A sequence may consist of all the files that make up the paper document (form 1 to form 5) or simply parts of it, depending on the type of request that is made to the authority (e.g. registration or variation). The sequences are numbered progressively starting from sequence 0000, which contains the complete dossier or its baseline. An eCTD can contain more than one sequence and is able to cover several production sites, different pharmaceutical forms or dosages of the same product and include all requests for renewals, variations, PSUR, ASMF made during the life cycle of the product.

How do I create a Technical Document?

The sequence is prepared (in technical jargon “set up”) through the use of a paid software approved throughout the European Union: Extedo eCTD manager. The program contains a series of folders and subfolders already organized according to the structure of the document, within which you go to load the various sections of the dossier. The position and nomenclature of each document is defined by the ICH and EMA guidelines. The sequence must be validated and then exported to the user’s network disks. Once set up, validated and extracted the sequence is presented to the authorities through a dedicated online portal. From this portal, the competent authorities can easily consult and safely download the complete dossier and all documentation related to the lifecycle of the registered product.

What are the advantages of this system?

The main advantages are two: it facilitates the exchange and storage of data and ensures that the content of the dossier remains unchanged from its preparation until its receipt by the authority.To facilitate the exchange of data, the program prepares the sequence according to the XML language (Extensible Markup Language). For a person who is totally foreign to the computer world, suffice it to say that it is a language used for the exchange of structured data. To ensure data security instead, the program inserts an “MD5 checksum” in the sequence to be transmitted. Always for “the less experienced”: a “MD5 checksum” is a sequence that uniquely identifies a file (a kind of fingerprint) and serves to check that a data exchange took place without loss of information and without undergoing changes.JSB Solutions can support the customer in the formatting of the dossier from paper to electronic format, in the creation of the dossier in electronic format and in the management of the entire life cycle of the dossier.