TOPRA Strategic Planning in Regulatory Affairs

Electronic Submissions
Strategic Implications

A presentation by Dr. Geoffrey Williams, Director, Regulatory

Operations, Daiichi Sankyo Development Ltd.

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes
At the end of this session the attendee should be able to:

Describe the key benefits and challenges for adopting

electronic submissions in the pharma industry

Describe the key components and differences between the

two commonest electronic submission formats: the eCTD and

NeeS formats

Understand the key challenges in developing a global

electronic submissions strategy

Describe the acceptability of the eCTD and electronic

submissions in the key global markets

In this presentation we will cover

What is an electronic submission?

What are the benefits and challenges to working with electronic submissions

What are the features and components of the main

formats?

What are the key considerations in developing a global

electronic submission strategy?

What is the current status of electronic submission

acceptance around the world?

Whats next in the electronic submission world?

Some conclusions

What is an electronic
submission?
Some files?
A copy of an MS Word file of a labelling
document

A PDF of a study report

A set of scanned images in a zip file
A set of PDF files with a linked Table of Contents
A full submission meeting the eCTD specification

What is an electronic
submission?
A

submission format?
Files on a CD or DVD
Files attached to an e-mail
Files submitted via Eudralink
Files submitted via CESP
Files submitted via a Gateway

What are the benefits of an

electronic submission?
A reduction/elimination of paper
Ease of navigation

An electronic Table of Contents (TOC)

Bookmarks
Hyperlinks
Easy to search or query

Searching for documents

Searching the content of the documents (full text search)
Easy to copy information
A means to relate the information in this dossier to
other submitted information
A means to relate this dossier to other dossiers
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What are the challenges of

electronic submissions?
Standards for the documents
Standards for the dossiers
The structure of the dossier
Technical validation of the submissions
The need for tools to be able to create
and manage the submissions
A technical understanding of the tools
and formats
For when things go wrong
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Document Standards
Basic standards for electronic documents are included
in the eCTD specification
Create documents from an electronic source and
convert this directly to PDF
Create templates for your documents to standardise
and control the content of the documents

This also makes conversion to PDF easier

Avoid scanning paper and dont get caught up in trying
to create searchable text (OCR)
Train your writers to use MS Word properly!

Most people have never been on a course about their main

authoring tool

Dossier standards: eCTD and

NeeS
The electronic Common Technical
Document (eCTD) and the Non-eCTD
eSubmission (NeeS) format are two of
the more widely used formats
The following slides provide more
detail about these submission formats

The eCTD
The eCTD is a specification for an electronic submission
created by the ICH
The concept of a common global electronic submission
format was an early topic for the ICH

Unfortunately, there was no global submission format, so the

electronic submission topic had to wait for the CTD to be
developed

The intention is to give a common format for the

electronic version of the CTD dossier

This means it has to accommodate all of the features of the

CTD

The common dossier structure provided by the CTD

AND
The regional content requirements

ICH have defined the common part but each region/country

must also define their pieces as well

10

eCTD Lifecycle Management

One of the key features of the eCTD is
Lifecycle Management
This is providing information about the
relationship of one document to another
Represented by the operation attribute
new, replace, delete and append

And the modified file attribute

And also providing information about the

relationship of one submission to another
Represented by related sequence attribute in the
envelope
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Main components of the eCTD

Leaf Documents

The files with the information

Mostly PDF files

Some data files, where required (mainly USA)

A Directory Structure

Somewhere to put all of the files

The XML Backbone

A way of managing all of the information about the submission and the
files in the submission, as well as the relationships to previously
submitted files and submissions

Supports

Provides
A Style sheet

A simple way to view

the information in the
submission

Agency Review Tools

The review environment for

the agency, displaying the
lifecycle management info
12

The eCTD folder structure

13

eCTD leaf files

14

The eCTD XML backbone

15

The NeeS submission format

The NeeS format was developed in Europe
and was intended as a stepping stone to the
eCTD
Use the same files and folders as the eCTD but
simplify the navigation by using a PDF TOC
with hyperlinks
What is not available is the lifecycle
management information
But note that the NeeS format is still a good
standard!
NeeS has also become a term used in many regions

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Main components of a NeeS

submission
Leaf Documents

The files with the information

Mostly PDF files
XXXXXXXXXXXXXXXXXXXXXXXXXXXX
Some data files, where required (mainly USA)

A Directory Structure

Somewhere to put all of the files

The XML Backbone

A way of managing all of the information about the submission and the
files in the submission, as well as the relationships to previously
submitted files and submissions

Supports

Provides
A Style sheet

A simple way to view

the information in the
submission

Agency Review Tools

The review environment for

the agency, displaying the
lifecycle management info
17

Main components of a NeeS

submission
Leaf Documents

The files with the information

Mostly PDF files

[Using the eCTD standards and file naming]

A Directory Structure

Somewhere to put all of the files

[The same structure as the eCTD]
A PDF Table of Contents

A way to navigate the structure to the individual content files

18

Developing a global electronic

submission strategy (1)
Accept that you are going to work electronically,
so make the changes to your processes and
standards to gain the most benefit from the
format

Invest in the tools (document management,

submission publishing tools and ancillary tools)
Implement the standards for the documents and
get the authors in the functions to own them
Prepare to implement the CTD for all of your old
products (and think baseline)
Fully adopt the eCTD as the starting point for all of
your submissions in all regions

19

Developing a global electronic

submission strategy (2)
Your objective will be to author and publish the
scientific and regulatory content only once
But do so in a way that maximises the way it can be reused

You will want to create content in an electronic

submission ready state
eSub ready content con usually be printed out easily, but its not easy to
take paper and include it in an electronic submission

You will want to develop the product (submission)

strategy in a way that maximises the ability to reuse
content
Write content so it can be reused in all regions
Look for ways to reuse one submission in another region (e.g. EU to
Switzerland, EU to Australia, etc.)

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Why adopt the CTD/eCTD?

These are the standards used most widely
ICH regions and more widely

The standards are a higher/highest common

denominator so the lower standards can
usually be easily created from the documents
and submissions
For example, the NeeS is a simplified eCTD, so if you can
create an eCTD you can create a NeeS

Even creating some of the other standards are easier if

you start with the CTD/eCTD (e.g. the ASEAN CTD)

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Standards where there are none

(published)
Having made the investment, use the document and
submission standards whenever you can
The standards for an electronic document make sense
whether there is a Marketing Application immediately
planned or not

Bad electronic documents are more difficult to use than bad

paper!

And it is extra effort to upgrade the documents later

Extrapolate from the eCTD and NeeS standards when
you are creating other submission types where there
might not be a published standard

CTAs in Europe and the rest of the world

Submissions for Scientific Advice, Paediatrics or Orphan Drug
Designation
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Use electronic submissions

whenever you can
I will talk about the documented acceptability
of electronic submissions around the world
However, most agency reviewers are now
used to working electronically
Even if their regulations say the submission
must be in paper, you can bet that they will
create their assessment report in MS Word
and e-mail it to you when they are done
Therefore, always put the electronic
submission into the package for the agency,
most reviewers will use it in preference to the
paper
23

Make your internal use part of

the strategy
A good electronic submission and well
authored documents are a valuable
resource to your company
Well managed documents will help
your own internal business
Combine these benefits in to your
strategy and ensure that your company
gets the most from the investment in
working electronically

24

Caveat 1: Do you have a global

product strategy?
The maximum reuse of content is only possible when
the product strategy is a global one
There may be good reasons for regional differences

Different regional guidance for the disease

Business decisions on partnering and licensing
Business decisions on sourcing and manufacture
But try and avoid internal issues leading to regionally
different content

Aim to write global overviews and summaries

Publish documents in a way that allows global reuse (particularly
CSRs)

25

Caveat 2: Product lifecycle grows

differently in each region
The strategy points I have discussed work best for the
first submission of the initial Marketing Authorisation
in each of the countries
This is the one time you can control the content and
choose to keep it as harmonised as possible
Thereafter the review processes and timelines, the
preferences and foibles of each reviewing agency and
the internal priorities will take over
However, continue to look for the opportunities to
create and reuse common content

26

Electronic submissions: Region

by region The United States (1)
The US FDA were the earliest adopters of the
concept of electronic submissions, both
informally and then more formally
The additional data requirements have made
the use of electronic submissions a necessity
The eCTD has been a requirement since 2007
Thankfully, the slight differences between
small molecule and biologics submissions
have been removed
But the NDA presubmission process can still
lead to some individual requests and
inclusions
27

Electronic submissions: Region

by region The United States (2)
The biggest difference is the handling of the data
Submissions require copies of CRFS and datasets from
the outset

Dont forget the Nonclinical datasets

Other additions (adjudication packages, Medwatch
forms, etc.) may be requested
The Nonclinical and Clinical reports must also be
submitted with a Study Tagging File (STF)

The STF is a mini XML backbone to manage the components of

each report

The Clinical tagging is defined in terms of the ICH E3 sections, so

it is easier if your templates use these sections

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Electronic submissions: Region

by region The United States (3)
The eCTD is also used in the IND phase
There is good business case for getting the benefit of the
lifecycle management capabilities of the eCTD in the IND

The FDA already allows for direct cross

referencing from the NDA eCTD back to
content first submitted as part of the IND

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Electronic submissions: Region

by region The United States (4)
Electronic submissions are made through the
FDA Electronic Submission Gateway (ESG)
making for a fully electronic process
Many of the largest initial NDA submissions will need to be
submitted on hard media

30

Electronic submissions: Region

by region EU (1)
The EU review processes and the autonomy of
the individual EU Member States makes this a
more complex environment to work in
However, the situation is a lot clearer now
than it was just two or three years ago
In addition, if you aim to optimise your
investment in eCTD and use this format
whenever you can then the number of issues
are very much reduced

31

Electronic submissions: Region

by region EU (2)
The Centralised Procedure

The eCTD has been the only acceptable format for the last four
years

Since March 2014 the use of the EMA Gateway has also been
mandated

The EMA has invested in providing the tools to review the eCTD
to all EU NCAs

Submission to the CHMP members in the NCAs is also getting

easier

Over one third of the NCAs will collect their copy of the submission

from the Central Repository

Over one third of NCAs will accept their eCTD via CESP
Leaving less than one third who still require copies on CD/DVD

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Electronic submissions: Region

by region EU (3)
The Mutual Recognition and Decentralised
Procedures
These procedures (and the NP) are more subject to the
individual whims of the NCAs

However, the eCTD is acceptable at all EU NCAs, in large

part to the experience gained from participating in the CP

There is specific guidance on how to use the eCTD in these

procedures

There is move to make the eCTD mandatory for both

procedures by the end of 1Q2018 (with all new MAAs in
DCP 3Q2015 and MRP 1Q2017)

33

eSubmission Roadmap
(reflecting final adopted version 1.0 dated 7th Nov 2014)
draft
eSub
Roadmap

NCA &
industry
survey

Ongoing/optional
Mandatory

eSub
Roadmap
Adoption

Use of eCTD v.4

All submissions in CP (human) in eCTD

New MAA in DCP (human) in eCTD

New MAA in DCP and MRP

(human) in eCTD

All submissions in MRP (human)

All other MRP submissions

(human)

Use of NeeS and eCTD in DCP and MRP (human)

All submissions in CP,

DCP and MRP (human) in
eCTD

New MAA in CP and DCP

(vet) in VNeeS

All submissions in CP, DCP and MRP (vet) in VNeeS

Use of VNeeS in CP, DCP and MRP (vet)

eGateway (CP)
(human and vet)

All other in CP and all

MRP submissions (vet)

Single submission portal - combined CESP/Gateway

in CP (human)

eGateway (CP, human)

Single submission portal - combined CESP/Gateway

in all other procedures (human and vet)

CESP (human and vet)

in CP

Use of eAF in all procedures (human and vet)

in all other
procedures

NCA use of Common Repository for CP submissions

(human)

eAF in all procedures (human and vet)

NCA use of Common Repository for all CP submissions

(human)

Use of PSUR Repository for CAPs

and NAPs (human)

2013

2014

eSubmission Roadmap Timelines

Single Submission Portal

with integration of eAF
for all submissions
(human and vet)

2015

2016

Use of PSUR Repository for all CAPs and NAPs

(human)

2017

2018

Electronic submissions: Region

by region EU (3)
National Procedures

The greatest challenge will come with products registered via the
National Procedures

These are generally old cash cow products that rely on a

minimal investment to maintain on the market

This has often meant only converting content to the CTD when
absolutely necessary, let alone the eCTD

Often these projects ae maintained on a national basis so the

investment for electronic submission tools may need to be made
outside the central R&D groups

They have been a prime candidate for the NeeS format, rather
than the eCTD because of the lower technical requirement

Note that the EU eSubmission Roadmap is silent on the subject

of mandatory eCTD in NP, but expect that it will come along at
some point
35

Electronic submissions: Region

by region EU (4)
Means of submission for MRP and DCP

The CESP portal is acceptable as a submission route in 26 EU

countries and has been a success in providing a simple way to
submit electronically to EU NCAs

Some countries still have other requirements but the message is

generally that electronic working is the way to go

Other submissions

The new CT regulation is likely to make an eCTA specification

much more of a reality

However, assume that it will use standards for documents already in

the eCTD

Many NCAs are looking at other submission processes and

starting to introduce electronic requirements (PSURs, Scientific
Advice, etc.)
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Electronic submissions: Region

by region Japan (1)
Marketing Applications
As ICH members, the PMDA have been adopters of the
eCTD, though at a slower pace than US and EU

The eCTD is not adopted for all submission types

Not used for generics and many CMC submission types

The eCTD lifecycle is not implemented in the same way

However, the eCTD is moving from an archive format to
a standard submission format without paper

37

Electronic submissions: Region

by region Other Regions (1)
Canada
Health Canada have been members of the ICH eCTD
Expert Working Group since the start

eCTDs have been acceptable since 2009 for Marketing

Applications (NDS)

Not acceptable for clinical trial submissions

Switzerland
Also founder members of the ICH eCTD EWG
SwissMedic will only accept the eCTD (there is no
equivalent to the NeeS)

However, the Swiss guidance follows the EU in many

places and allow for the easy creation of the initial MAA
submission

38

Electronic submissions: Region

by region Other Regions (2)
Australia

The TGA have recently joined the ICH eCTD EWG to support their
eCTD implementation project

There is currently a pilot running for companies to submit eCTDs

Certain categories of MA submissions only
Due to finish in Feb 2015, but likely to accept eCTDs upon
request

Removes the need to produce vast amounts of paper

Saudi Arabia

The SFDA is very active at the moment in implementing the

eCTD

Not without issues (e.g. the need for baselines for all products)
Not yet clear how this affects other GCC states, though UAE,
Oman and Bahrain have shown interest as well

39

Electronic submissions: Region

by region Other Regions (3)
South Africa
The MCC have also been running a pilot with the eCTD
The plans for further adoption are not so clear

Thailand
The Thai FDA have also been running an eCTD pilot

Turkey
Turkey have talked about a NeeS for eCTD, but using
folders named in Turkish

Making all the links in all of the files we created for the eCTD
invalid

40

Electronic submissions: Region

by region Other Regions (4)
The ASEAN Countries

Annoyingly, the ASEAN countries decided not to adopt the ICH

CTD, despite being associate members of ICH through the ICH
Global Cooperation Group

The ASEAN CTD basically follows the ICH CTD structure, but
they renumbered it into 4 modules

The ASEAN countries have also pushed the use of the ASEAN
CTD over the ICH CTD

There is also now talk of them producing an ASEAN eCTD

based on the ASEAN CTD

However, the use of the basic ICH CTD structure means it is an

administrative change to the documents, rather than anything
more complicated
41

Electronic submissions: Region

by region Other Regions (5)
Other Countries
Many other countries will accept CTD format submissions,
including the following agencies

Hong Kong, Singapore, China, Taiwan, Mexico, Brazil,

Argentina

Many other countries accept electronic filings based on

their local requirements (NeeS like submissions)
Russia, Turkey, Egypt, India, Israel, Malaysia, South Korea,
Mexico, Venezuela, Bosnia Hercegovinia

All of this means that if we work from the high level

standards of the eCTD we can work back to the standards
acceptable in these countries, and most reviewers would
probably like to receive an electronic submission

42

Whats next? (1)

The ICH have been working on eCTD v4.0 for over 5 years
The development is a collaboration with ISO and HL7 which
should lead to a technical standard that is also an
internationally recognised standard
This offers many more possibilities to see the eCTD adopted
by agencies
eCTD v4.0 is intended to address a number of business
scenarios where the current eCTD specifcation (v3.2.2)
struggles

Particularly some of the more complex EU procedures for Grouping and

Worksharing in the MRP/DCP

Also more flexibility in extending the standard to other non-CTD

submission structures

The initial signoff is due in late 2015 with implementation

activities beginning in 2016
43

Whats next? (2)

We should expect to see the electronic transmission of
data increase with more portals and gateways
The content of the dossier will become more structured
with standards introduced for the data
Electronic Application Forms to improve the uploading and processing of
submissions

Structured content to drive compliance for documents like labelling (e.g.

SPL in the US)

Eventually, we may see two way communication

between applicant and regulator, with the flow in both
directions fitting together to show relationships and
approval status

44

Conclusions
The acceptance of electronic submissions has been
increasing rapidly over the past two or three years
The rapidly increasing document and data
requirements of regulatory agencies for the content of
their dossiers is a significant driver for this change
This is no longer something that only matters in the
ICH regions, some of the keenest adopters are in the
growing markets who see technology as a way to
challenge and keep up with the bigger agencies
Industry needs to accept this change and embrace it
The key is making the management of electronic
documents and submissions a key part of our internal
information management strategy (eSubs are no longer
just something we create for regulators)
45

Conclusions
We are still a long way from having a single format that
is acceptable across the whole world (if this was ever a
real possibility)
However, the willingness of the regulators to accept
electronic ways of working allows industry to develop
more coherent strategies for electronic submissions
Look to move to the highest specification you can
support as this will be most flexible in meeting the
needs across all countries, and also sets you up for the
future

46

In this presentation we covered

What is an electronic submission?

What are the benefits and challenges to working with electronic submissions

What are the features and components of the main

formats?

What are the key considerations in developing a global

electronic submission strategy?

What is the current status of electronic submission

acceptance around the world?

Whats next in the electronic submission world?

Some conclusions

47

Recommended references
ICH

http://www.ich.org/products/electronic-standards.html

US

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/F

ormsSubmissionRequirements/ElectronicSubmissions/ucm15
3574.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/F

ormsSubmissionRequirements/ElectronicSubmissions/UCM08
5361
Europe

http://www.ema.europa.eu/ema/index.jsp?curl=pages/abo

ut_us/general/general_content_000116.jsp&mid=WC0b01ac
0580028c2b

http://esubmission.ema.europa.eu/index.htm
48

Recommended references
Canada

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-

demande/guide-ld/ectd/index-eng.php
Switzerland

https://www.swissmedic.ch/zulassungen/01520/01662/ind

ex.html?lang=en
Other Regions Australia

http://www.tga.gov.au/australian-ectd-submissions

Other Regions Saudi Arabia

http://www.sfda.gov.sa/en/drug/drug_reg/Pages/drug_reg

.aspx?catid=2

49

Recommended references
Other Regions South Africa

http://www.mccza.com/dynamism/default_dynamic.asp?grp

ID=30&doc=dynamic_generated_page.asp&categID=178&gr
oupID=30#A focus on ZA CTD
Other Regions Thailand

http://drug.fda.moph.go.th/eng/e_submiss.asp

ASEAN CTD Specification

http://www.hsa.gov.sg/content/dam/HSA/HPRG/Western_

Medicine/Overview_Framework_Policies/Guidelines_on_Dru
g_Registration/ACTD_OrganizationofDossier.pdf

50

QUESTIONS?

51

Acknowledgements
The EFPIA members of the ICH M8 EWG
The members of the EFPIA eCTD Topic Group

Contact details
Name: Geoff Williams
Email: gwilliams@dsd-eu.com

52