Copyright © 2020 pepgra. All rights reserved 1

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

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.

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

Copyright © 2020 pepgra. All rights reserved 3

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.