e-Dossier Submission: Regulatory and Procedural Guidance for Pharmaceutical Companies

E-DOSSIER SUBMISSION: REGULATORY AND PROCEDURAL GUIDANCE Dr. Nancy Agens, Head, Technical Operations, Pepgra

In Brief This particular write-up presents a background about e-dossiers that are submitted to regional authorities by pharmaceutical companies for drug registrations. The write-up highlights the pre-requisites and procedures while submitting an e-dossier.

Keywords: e-dossiers, eCTD, electronic submissions, ICH, MHRA, I. INTRODUCTION Right from 1990, the International Conference for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has been consistently striving to develop a framework which is standardized with regards to drug registrations. The objective of such a standardized framework is to bring about a harmony to the maximum extent possible, the content and structure of the technical information furnished to lend support to marketing authorizations. Representatives from Japan, the European Union and the United States and from other regions that function as observers are instrumental in driving the ICH. The steering committee of the ICH during November 2000 had ratified guidelines which were established by the ICH M4 working group, elucidating the Common Technical Document (CTD) in order to register pharmaceuticals that were intended for use by humans (Bonn, 2007).

This implied that the paper version of the CTD had realized Step 4 status, indicating that the ICH members had reached a Copyright Š 2020 pepgra. All rights reserved

consensus wherein each member was committed to integrate the ICH guidelines within the regulatory framework of each region. Culmination of this last step is termed as Step 5. Within the United States (US), the FDA has officially embraced the guidelines as laid down by the ICH as FDA guidance. Within Europe, Volume 2B of Notice of Applicants underwent modifications during 2001 to incorporate the CTD within the legislative system in Europe. From July 2003 onwards, it has been made mandatory for every applicant to submit paper dossiers in the EU, Japan and the US. However, a growing need was felt for facilitating electronic submissions. The ICH M2 ESTRI (Electronic Standards for the Transfer of Regulatory Information) working group created the standard for electronic message exchange for CTD which was termed as the electronic common technical document (eCTD). The eCTD comes across as an electronic form of a CTD that was paper based. The eCTD specification outlines the criteria to take into account electronic submissions as technically acceptable. In addition, the standards as laid down by the eCTD outline the mediums to develop and convey an electronic submission that matches the CTD definitions (Bonn, 2007). The focus here is to offer the capability to convey the CTD from industry to a regulatory authority.

Also, the eCTD considers the necessity to extend assistance over the entire lifecycle of an electronic submission or dossier. The eCTD standard founded on the initial version 3.0 specification realized Step 4

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during October 2002, and is being executed across regions, escalating it to Step 5.

Therefore, the objective of this article is to outline the regulatory and procedural guidance for e-dossier submission.

II. FUNDAMENTALS OF ELECTRONIC SUBMISSION The specification for eCTD elucidates the format for the message and the procedure for moving submission documents and processing instructions to an agency system. Standards as laid down by the eCTD offers a medium to capture every interaction that occurs between agencies and industry, in such a way that it sheds light on modifications between multiple submissions. This lifecycle view of the submission can be realized with the help of the XML format. By using the XML format, it is possible to describe every document that is included within the submission. In addition, it also offers instructions to the system that receives the submission, thus enabling data management, which elucidates the submission. Such data is popularly known as meta data and examples of meta data at the level of submission comprises information pertaining to the submission type, the agency that will receive the submission and the applicants who submit (FAMHP, 2016). Examples pertaining to meta data at the level of document would comprise of information regarding the version, descriptive information as in name of documents and time stamps and language.

On the whole, the ability of the XML to segregate content from structure holds the key in terms of its versatility and increasing popularity. It has several uses, enabling users to restyle and reformat to match diverse media types, recognize elements, reuse portions, exchange data and sustain and output several versions for the same document.

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As an outcome, extra specifications have been setup by several regions on the basis of XML format for content in the eCTD standard. These are frequently replace document files that are unstructured (eg; doc, -pdf, -rtf) with XML documents that are highly structured and exemplified by the FDA’s Study Tagging File (STF) or Europe’s electronic Application Form (eAF), in tandem with initiatives at labeling like the FDA’s structured product labeling (SPL) and EMEA’s product information management (PIM). This trend can also be viewed as a consistent extension of the eCTD standard making the submitted information largely granular and more in a position to be managed with ease by systems which are automated. This, more often augments the efficiency and quality of the process of regulatory review.

II. ACCEPTANCE OF E-DOSSIERS The NCA Medicines and Healthcare products Regulatory agency (MHRA) in the UK has been since 2005 accepting electronic submissions while the paper format has been completely stopped since 2007. As a matter of fact, MHRA has made eCTD a mandatory requirement. While Belgium has embraced eCTDs largely, they still accept other formats. The same holds true for the Netherlands, Norway, Germany, Sweden, France, Denmark, Ireland and Austria. For nations like Romania, Cyprus, Spain, Czech Republic, Finland, Iceland, Lithuania, Latvia, Poland, Bulgaria, Estonia, Greece, Italy, Slovak Republic, Hungary, Liechtenstein, Luxembourg, Malta and Slovenia, no information is available with regards to eCTD standards.

III. CONCLUSION Application of the eCTD standard within the XML format tends to allow an 2

applicant’s submission documents to be reused within diverse regional markets. The submission is made up with five key modules wherein the first module comprises of all documentation specific to the region.

Exchange of this very initial module with a module pertaining to another agency enables a highly effective re-submission process across diverse markets, without feeling the need to modify the documentation or the meta data from the rest of the four modules.

Yet another benefit is that by creatively utilizing XML meta data, it is possible to outline the table of contents in different manners, enabling an application to have views that are specific to discipline (for instance; clinical vs. chemistry), lifecycle views that are cumulative which reveals every document and its existing state, views that are specific to submission revealing only the delta amongst submissions, module specific views etc., every additional particulars encouraging assembly efficiency and reviews.

REFERENCES [1]

Bonn (2007). Electronic Submission and the MRP/DCP: How to Compile a Dossier That Will be Accepted at the European Agencies. [Online]. der Rheinischen Friedrich-Wilhelms. Available from: https://dgra.de/media/pdf/studium/masterthesis/mast er_benning_l.pdf.

[2] FAMHP (2016). eSubmission Guidelines. [Online].

Available from: https://www.famhp.be/sites/default/files/downloads/ eSubmission Guideline revision 2 13final30102015.pdf.

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