Session A

eCTD - a global approach

Michael Gessert Product Manager Global Review & Validation

Dr. Gerhard Neurauter Director Regulatory Competence Center

14/15. February 2013

Agenda

20.02.2013 2 EXTEDO Confidential

… from paper CTD to an electronic eCTD on CD/DVD

eCTD Guidelines

Differences of eCTD over different regions

eCTD today and beyond

Benefits of eCTD

eCTD in industry and agencies (submission process overview)

eCTD at Agencies – Europe

… from paper CTD to an electronic eCTD on CD/DVD?

3

CTD – Common Technical Document

Before the introduction of the "Common Technical Document" (CTD):

• dossiers for Marketing Authorization Applications (MAAs) had to be

structured according to different, region- or country-specific specifications

(e.g. "old NtA"-format for Europe)

• poor synergy in dossier creation for different regions

• Poor comparability of dossiers for different markets

ICH – International Conference on Harmonization

ICH !

ICH – International Conference on Harmonization

eCTD !

ICH – International Conference on Harmonization

eCTD !

CTD – Common Technical Document

"OBJECTIVE OF THE GUIDELINE

This guideline presents the agreed upon common format for the preparation of a

well-structured Common Technical Document for applications that will be sub-

mitted to regulatory authorities.

A common format for the technical documentation will significantly reduce the time

and resources needed to compile applications for registration of human

pharmaceuticals and will ease the preparation of electronic submissions. Regulatory

reviews and communication with the applicant will be facilitated by a standard

document of common elements. […]"

source: http://www.ich.org/LOB/media/MEDIA554.pdf

CTD – Common Technical Document

Mind: The CTD specifications focus on paper based dossiers

and submissions. Yet, they are the basis for any current

electronic submission standard!*)

*) few exception: e.g. e-submissions for veterinary products are still based on "old NtA-format"

The CTD-Triangle

source: http://www.ich.org/products/ctd.html

The structure

of the

Common

Technical

Document

(CTD)

is usually illustrated

by means of a

triangle ...

The CTD-Pyramid

... or by means of a pyramid.

The CTD pyramid!

The CTD-Pyramid

The CTD is organised in

five Modules,

(M1, M2, M3, M4, M5).

The pyramidal structure

reflects the inter-dependence

of the modules' content.

The (physical) extend of each

section of the pyramid

roughly represents

the size of each of the

Modules.

The CTD pyramid

technical Components of the CTD: Binders

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

2 2 2 2 2 2 2 2 2 2 2 2

1 1 1 1 1 1 Example for an initial

marketing authorization

application for a new

drug in Europe

(average - for only 1 agency)

M1: 5 binders

M2: 10 binders

M3: 13 binders

M4: 45 binders

M5: 902 binders

total: 975 binders

For paper based dossiers, a stepped pyramid might be a better representation ;-)

technical Components of the CTD: Modules

M1: Administrative Information and Prescribing

Information (regional!)

M2: Common Technical Document Summaries

M3: Quality

M4: Nonclinical Study

Reports

M5: Clinical Study

Reports

technical Components of the CTD:

Modules' Tables of Content

Each CTD Module includes a Module- or even submission-wide Table of Contents

(Module ToC)

Section 1.1: comprehensive

(submission wide) ToC

Section 2.1: ToC com-

prising Modules 2 - 5.

Sections 3.1, 4.1, 5.1:

ToCs for the respective

Modules

for details see: Notice to Applicants, Volume 2B, Medicinal products for human use,

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/b/update_200805/ctd_05-2008.pdf

technical Components of the CTD: Sections

• Each Module of the CTD is divided into CTD-sections and CTD-subsections.

• Each CTD-section and CTD-subsection is defined by a CTD-structure number

and a CTD title.

examples taken from:

Notice to Applicants, Volume 2B, Medicinal products for human use, http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/b/update_200805/ctd_05-2008.pdf

CT

D-s

ec

tio

n/

su

bs

ec

tio

n

CTD-section/-subsection title

CTD-structure number

technical Components of the CTD: Documents

• CTD-sections and CTD-subsections

are composed of documents.

• "A document is defined for a paper

submission as a set of pages,

numbered sequentially and separated from

other documents by a tab." *)

*) cited from "ICH HARMONISED TRIPARTITE GUIDELINE ORGANISATION OF THE COMMON TECHNICAL DOCUMENT

FOR THE REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE M4.

tab sheet sequential page numbers

technical Components of the CTD: Documents

Documents are internally structured

by means of document sections

and subsections, identified by

headings and subheadings.

technical Components of the CTD: Documents

Documents of a certain complexity

should be equipped with an individual

Table of Contents (ToC),

and if appropriate a

Table of Figures (ToF) and/or a

Table of Tables (ToT).

CTD CTD – Different CTDs for Different Regions

Even though the CTD has largely enhanced the degree of

harmonization between MAAs in different countries/regions,

it is still not possible to use the same CTD across borders.

Each country/region requires specific adjustments to the content

of the CTD .

Only carefully selected parts of a CTD can be reused for

the individual MAAs.

CTD CTD: the Module 1 Issue

ICH defines the detailed structure for

Modules 2 – 5, only!

The structure for Module 1 is defined

by the respective ICH region

(or country)!

CTD CTD: Modules 2 - 5

CTDs for different regions/country may differ in content, due to

• different interpretation of what information should be located

in which CTD section (e.g. Module 2: EU US)

• different language requirements (e.g. EU = US JP)

• different manufacturing details in individual countries/regions

(e.g. specifications compliant to Ph.Eur. in EU but

compliant to USP in US)

• different extend of required source data

(e.g. Module 5: US > EU)

CTD CTD: CTD outside ICH

A number of countries outside the three ICH regions (EU, US, Japan)

have adopted the CTD structure for national MAAs and have developed

their own respective Module 1 structure, e.g.:

. . .

Switzerland Canada MCC Australia

Content related differences as described above do also occur for

these countries.

CTD Guidelines & Specifications: ICH (Modules 2 – 5)

Historical changes

M4 (R3): Organisation (including Revised Granularity Annex)

(Sept 2002/Jan 2004) & The M4 General Q&As (R3)

provides general information on principle CTD structure and granularity

•M4Q (R1): Quality & The M4 Quality Q&As (R1)

(Sept 2002/Jul 2003)

provides detailed information on principle CTD structure and content of Module 3

and Section 2.3 (QOS)

•M4S (R2): Safety & The M4 Safety Q&As (R2)

(Sept 2002/Nov 2003)

provides detailed information on principle CTD structure and content of Module 4

and Sections 2.4 and 2.6

•M4E (R1): Efficacy & The M4 Efficacy Q&As (R4)

(Sept 2002/Jun 2004)

provides detailed information on principle CTD structure and content of Module 5

and Sections 2.5 and 2.7

•E3: Structure and Content of Clinical Study Reports (Nov 1995)

provides detailed information on principle structure, content and granularity of

Module 5 Study Reports

CTD Guidelines & Specifications, EEA

EU/EEA Module 1 and European Interpretation of ICH Specifications for Modules 2 – 5): Notice to Applicants Volume 2B, incorporating the CTD (May 2008) & Q&A-document http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/eudralex/vol-2/index_en.htm

CTD Guidelines & Specifications, US

US Module 1 and US Interpretation of ICH Specifications for Modules 2 – 5): See FDA-website at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.htm

From CTD to eCTD?

27

eCTD - Essentials

"the world is a

disc!" "electronic submission"

"online submission"

• in most cases "electronic submissions"

are transferred to agencies by means

of discs like CDs or DVDs shipped by

post or courier

• only few agencies allow "online

submission" e.g. via e-mail or upload

to specific agency web-portals

• this is also an issue of submission size

(MByte, GByte, …) and network

bandwidth (Mbit/sec)

From paper to electronic – why?

e-Submission

p-Submission

e!

From paper to electronic – why?

agency perspective industry perspective

• reduction of physical paper flow and physical archival space

• reduction of printing and shipping

costs

• easy navigation through and

review of the dossier

• easy retrieval of submitted

documents

• easy creation of assessment

reports via copy & paste

• reuse of documents or partial-

submissions for other dossiers

• submission-/dossier-/

agency-wide searchability for

keywords/topics

• better integration into existing

"electronic" workflow

• easier submission lifecycle manage-

ment

• easier access to the

current status of documentation

!

The birth of the eCTD and eCTD specifications

to adopt CTD specifications to the requirements of electronic submission,

additional "technical" specifications had to be defined, addressing issues

like e.g.:

• file formats to be used

• naming conventions for files and directories

• (how) should directory structure reflect CTD structure

• navigation through the electronic dossier

• ... .

these specifications are referred to as eCTD specifications

eCTD – specifications: ICH (international)

since ICH CTD specification does only cover Modules 2 – 5 (Module 1

remains in the responsibility of the individual ICH regions), ICH eCTD

specifications are restricted to Modules 2 – 5, too.

available for download at: http://estri.ich.org/eCTD/eCTD_Specification_v3_2_2.pdf

eCTD – specifications: NCA (national)

Module 1 eCTD specifications for the individual ICH regions (and other

countries) can be downloaded from the respective agencies' websites.

A link list is also provided at http://estri.ich.org/eCTD/index.htm :

eCTD – worldwide

Source: 3/ 2012

eCTD – worldwide

Source: 3/ 2012

Folders

eCTD – files & directories

"The documents of a submission as PDF-files, named and located in a directory

structure in such a manner as to reflect the CTD outline, …"

documents as PDF-files

directory structure matches

CTD-structure

directory and file names as defined by

eCTD-specifications

eCTD – files & directories Variables in Specification

• In some cases, eCTD-specifications do not explicitly define the naming of a file

or directory, but only describe how it should be formed (examples below from

ICH eCTD spec. 3.2.2 and EU Module 1 spec 1.4):

• Names in italics are variable and should be adjusted for each application while

regular text has to be taken literally.

• "excipient-1" should therefore be replaced by the name of the respective excip-

ient, and "product-1" by the description of the product. (See example on next slide.)

• such variable names, or part of names, are frequently found in all Modules, e.g.

(example:m1/eu/12-form/uk/uk-form-250mg.pdf)

eCTD – files & directories

top-level directory

• identifies the product/dossier to which the submission belongs

• is usually derived from the product description, the procedure

number (Europe), or a pre-assigned application number (US)

– details depend on the type of product, procedure, involved

agency, … .

• similar procedure in ZA

sequence directory

• is always a four digit number

• is 0000 for the initial eCTD-submission for a product

• is increased by one for each new sequence submitted

"util" directory with "dtd" and "style" subdirectories

• contain technical auxiliary files, like "DTDs" and "Stylesheets"

• are mandatory for eCTD submissions

eCTD – files & directories

For the excipient "marshmallow extract" of a product described as

"Useless Pills iii 250" (product name),

"iii pills 250mg/1ng" (pharmaceutical form and strength)

manufactured by the company "Placebo Ltd"

the 32P-structure could look like that:

Folders

Mind the effect of the variable parts on the total path length!

Folders

eCTD – files & directories

There's more in the directory structure, than just the CTD outline:

top-level directory (product/dossier description)

sequence directory

util directory & sub-directories

eCTD – files & directories

contents of the "util"-folder:

content of the index-md5.txt checksum file:

eCTD – XML-backbone

" … with XML-Files acting as Tables of Contents … ."

Folders

Folders

There are to be at least two xml-files in

each eCTD-submission*)!

index.xml always located in the sequence

folder and accompanied by its

md5-checksum file.

xy-regional.xml always located in the

xy (region-) subfolder of Module 1.

*) There can be more, e.g. when using study-tagging files or electronic application forms.

eCTD – XML-backbone

double mouse click

on an xml-file usually

opens it in your

web browser

the index.xml can

be regarded as

"your

submission's

homepage"

For each file/document

of your submission

there's a hyperlinked

entry in the xml-files

A mouse click on any

of the blue underlined

links will launch your

(pdf) viewer and display

the respective document

eCTD – XML-backbone

there's more than hyperlinks in an xml-file: additional information on the

linked files ("meta data"):

[lifecycle operators]

(new, append, replace, delete)

[content related attributes]

(e.g. on manufacturers, drug products,

drug substances, indications, study report numbers,

… )

eCTD – XML-backbone

Not all hyperlinks in the index.xml open a PDF-file. The Module 1 link just

opens the xy-regional.xml. The xy-regional.xml file contains

more, region specific meta data

on the submission, e.g.

submission type,

applicant name,

procedure number,

related sequences,

… .

The section where this meta data

is kept is called "envelope".

Envelope information can also

be found in the cover letter

and/or application form. But these

documents are meant to be read

by humans. The envelope is

"machine-readable".

eCTD – bookmarks & hyperlinks

"hyperlink" hyperlinks are navigation aids, allowing

the reader to "jump" from a source

location (e.g. literature citation) in the

submission to a target destination

(e.g. the literature document referenced

in the text).

"internal hyperlink" source location and target destination

are within the same document

"external hyperlink" source location and target destination

are not within the same document

eCTD – bookmarks & hyperlinks

"bookmark" Bookmarks are a specific feature of

Adobe®–PDF-Files.

They can be regarded as hyperlinks

without a source location inside the

document.

Bookmarks usually reflect the structure

of the document's table of contents.

eCTD – bookmarks & hyperlinks

Hyperlinks in the document's ToC (blue boxes)

Bookmark for each ToC-

entry

49

eCTD in industry and agencies (submission process overview)

Knowledge. Performance. Success.

Confidential Information 50

Authorities

Industries

Internal

processes

Internal

processes

eCTD Reviewing Software

eCTD Compilation & Publishing SW

eCTD Format

Specification

eCTD Conformity

Test SW

Submission Process Overview

Required tools to establish an eCTD process

20.02.2013 51 EXTEDO Confidential

Compiling / Publishing tool – Industry

e.g. eCTDmanager

Validation Tool – Industry & Agency

GLOBALvalidator

Reviewing Tool – Agency

EURS is Yours

Danke

Baie Dankie

Ngiyathokoza

Ke a leboha

Ke a leboga

Siyabonga

Inkomu

Ndo livhuwa

Ro livhuwa

Enkosi

Ngiyabonga

Thank You