Lecture+7+-++G+Williams

TOPRA Strategic Planning in Regulatory Affairs

Electronic Submissions

Strategic Implications

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSIONENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSIONENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

A presentation by Dr. Geoffrey Williams, Director, Regulatory Operations, Daiichi Sankyo Development Ltd.

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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

Learning Outcomes

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

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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?

In this presentation we will cover

electronic submission strategy?

What is the current status of electronic submission acceptance around the world?

Whats next in the electronic submission world?

Some conclusions

3

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 scanned images in a zip file

A set of PDF files with a linked Table of Contents

A full submission meeting the eCTD specification

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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

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A reduction/elimination of paper

Ease of navigation

An electronic Table of Contents (TOC)

Bookmarks

Hyperlinks

What are the benefits of an electronic submission?

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 dossiers6

Standards for the documents

Standards for the dossiers

The structure of the dossier

Technical validation of the submissions

What are the challenges of electronic submissions?

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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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

Document Standards

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

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The electronic Common Technical Document (eCTD) and the Non-eCTDeSubmission (NeeS) format are two of the more widely used formats

The following slides provide more

Dossier standards: eCTD and NeeS

The following slides provide more detail about these submission formats

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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

The eCTD

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

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

eCTD Lifecycle Management

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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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

Main components of the eCTD


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

A Style sheet

A simple way to view the information in thesubmission

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Agency Review Tools

The review environment forthe agency, displaying thelifecycle management info

Provides Supports

The eCTD folder structure

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eCTD leaf files

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The eCTD XML backbone

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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

The NeeS submission format

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 regions16

Leaf Documents


Mostly PDF files

Some data files, where required (mainly USA)



Main components of a NeeSsubmission

XXXXXXXXXXXXXXXXXXXXXXXXXXXX


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

A Style sheet

A simple way to view the information in thesubmission

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Agency Review Tools

The review environment forthe agency, displaying thelifecycle management info

Provides Supports

Leaf Documents


Mostly PDF files

[Using the eCTD standards and file naming]



Main components of a NeeSsubmission


[The same structure as the eCTD]

A PDF Table of Contents

A way to navigate the structure to the individual content files

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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,

Developing a global electronic submission strategy (1)

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

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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

Developing a global electronic submission strategy (2)

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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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

Why adopt the CTD/eCTD?

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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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

Standards where there are none (published)

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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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

Use electronic submissions whenever you can

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

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A good electronic submission and well authored documents are a valuable resource to your company

Well managed documents will help your own internal business

Make your internal use part of the strategy

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

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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

Caveat 1: Do you have a global product strategy?

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)

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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

Caveat 2: Product lifecycle grows differently in each region

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

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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

Electronic submissions: Region by region The United States (1)

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

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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, Medwatchforms, etc.) may be requested


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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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


content first submitted as part of the IND

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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


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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

Electronic submissions: Region by region EU (1)

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

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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


The EMA has invested in providing the tools to review the eCTDto 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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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


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)

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eSubmission Roadmap

(reflecting final adopted version 1.0 dated 7th Nov 2014)

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

All submissions in CP,

DCP and MRP (human) in

eCTD

Ongoing/optional

Mandatory

Use of eCTD v.4

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

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

All submissions in MRP (human)

New MAA in DCP and MRP

(human) in eCTD

All other in CP and all

MRP submissions (vet)

New MAA in CP and DCP

(vet) in VNeeS

All other MRP submissions

(human)

All submissions in CP (human) in eCTD

draft

eSub

Roadmap

NCA &

industry

survey

eSub

Roadmap

Adoption

eSubmission Roadmap Timelines

2013 2014 2015 2016 2017 2018

Use of eAF in all procedures (human and vet)

Single Submission Portal

with integration of eAF

for all submissions

(human and vet)

CESP (human and vet)

eGateway (CP)

(human and vet)eGateway (CP, human)

NCA use of Common Repository for all CP submissions

(human)

NCA use of Common Repository for CP submissions

(human)

Single submission portal - combined CESP/Gatewayin all other procedures (human and vet)

in CPeAF in all procedures (human and vet)

Use of PSUR Repository for all CAPs and NAPs

(human)

Use of PSUR Repository for CAPs

and NAPs (human)

Single submission portal - combined CESP/Gatewayin CP (human)

in all other procedures

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


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

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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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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

Electronic submissions: Region by region Japan (1)

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

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Canada

Health Canada have been members of the ICH eCTDExpert Working Group since the start

eCTDs have been acceptable since 2009 for Marketing Applications (NDS)

Electronic submissions: Region by region Other Regions (1)

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

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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


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

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


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 eCTDinvalid

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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

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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


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

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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

Whats next? (1)

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

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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

Whats next? (2)

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

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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

Conclusions

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)

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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

Conclusions

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

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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

In this presentation we covered

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

ICH

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

US

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.htm

Recommended references

3574.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM085361

Europe

http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000116.jsp&mid=WC0b01ac0580028c2b

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

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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/index.html?lang=en


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

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Other Regions South Africa

http://www.mccza.com/dynamism/default_dynamic.asp?grpID=30&doc=dynamic_generated_page.asp&categID=178&groupID=30#A focus on ZA CTD

Other Regions Thailand

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


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_Drug_Registration/ACTD_OrganizationofDossier.pdf

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QUESTIONS?

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Acknowledgements

The EFPIA members of the ICH M8 EWG

The members of the EFPIA eCTD Topic Group

Contact details

Name: Geoff Williams

Email: [email protected]

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